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BMS2052 > Antimicrobials: Agents, Resistance and Design > Flashcards

Antimicrobials: Agents, Resistance and Design Flashcards

1
Q

Define

Acquired resistance

A

occurs when a particular microorganism obtains the ability to resist the activity of an antimicrobial agent to which it was previously susceptible

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2
Q

Define

ADMET

A

Initialism of absorption, distribution, metabolism, excretion, toxicity: A set of test categories used together in drug discovery to provide insight into how a pharmaceutical drug interacts with the body as a whole

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3
Q

Define

Aminoglycosides

A

any of a group of antibiotics (as streptomycin and neomycin) that inhibit bacterial protein synthesis and are active especially against gram-negative bacteria

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4
Q

Define

Antimicrobial agents

A

A general term for drugs, chemicals, or other substances that either kill or slow the growth of microbes

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5
Q

Define

Bactericidal

A

an agent that kills bacteria

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6
Q

Define

Bacteriostatic

A

an agent that prevents the growth of bacteria

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7
Q

Define

β-lactamases

A

enzymes produced by bacteria that provide multi-resistance to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems (ertapenem),

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8
Q

Define

β-lactams

A

a class of antibiotic consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, carbapenems and carbacephems

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9
Q

Define

Cephalosporins

A

a large group of antibiotics derived from the mold Acremonium. They are bactericidal (kill bacteria) and work in a similar way to penicillins

How well did you know this?
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10
Q

Define

Colistin

A

an antibiotic produced by certain strains of the bacteria Paenibacillus polymyxa. It is effective against most Gram-negative bacilli

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11
Q

Define

Fidaxomicin

A

an oral macrolide antibiotic labeled for the treatment of Clostridium difficile–associated diarrhea in adults

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12
Q

Define

Fluoroquinolones

A

any of a group of fluorinated derivatives (such as ciprofloxacin and levofloxacin) of quinolone that are used as antibacterial drugs

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13
Q

Define

Forward pharmacology

A

the traditional approach to discovering new drugs. Typically, a library of chemical compounds is screened for causing a desired phenotype in cells / tissue

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14
Q

Define

High-throughput screening

A

recent scientific methods relevant to the field of chemistry and biology, in which hundreds of thousands of experimental samples are subjected to simultaneous testing under given conditions

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15
Q

Define

Hit to lead

A

a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds

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16
Q

Define

Horizontal Gene Transfer (HGT)

A

the movement of genetic material between unicellular and/or multicellular organisms other than by the (“vertical”) transmission of DNA from parent to offspring (reproduction)

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17
Q

Define

In silico screening

A

Producing and screening drug candidates on a computer or via computer simulation

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18
Q

Define

Intrinsic resistance

A

a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic

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19
Q

Define

Klebsiella pneumoniae carbapenemase (KPC)

A

a group of emerging highly drug-resistant Gram-negative bacilli causing infections associated with significant morbidity and mortality

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20
Q

Define

Lead optimisation

A

the process by which a drug candidate is designed after an initial lead compound is identified

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21
Q

Define

Macrolides

A

a class of antibiotic that includes erythromycin, roxithromycin, azithromycin and clarithromycin. They are useful in treating respiratory, skin, soft tissue, sexually transmitted, H. pylori and atypical mycobacterial infections

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22
Q

Define

Mobilised colistin resistance (MCR)

A

a gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections

How well did you know this?
1
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2
3
4
5
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23
Q

Define

New Dehli metallo-β-lactamase

A

an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections

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24
Q

Define

Nosocomial infections

A

infections that have been caught in a hospital and are potentially caused by organisms that are resistant to antibiotics

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25
Q

Define

Omp protein

A

a protein involved in signal transduction. It is a highly expressed, cytoplasmic protein found in mature olfactory sensory receptor neurons of all vertebrates

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26
Q

Define

Oxazolidinones

A

a novel class of synthetic antimicrobial agents unrelated to any other antibacterial drug class. They were originally developed as monoamine oxidase inhibitors for treatment of depression, with subsequent recognition of their antimicrobial properties

How well did you know this?
1
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2
3
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5
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27
Q

Define

Penicillin

A

an antibiotic or group of antibiotics produced naturally by certain blue molds, and now usually prepared synthetically

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28
Q

Define

Pharmacodynamics

A

what the drug does to the body

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29
Q

Define

Pharmacokinetics

A

what the body does to the drug

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30
Q

Define

Porin protein

A

beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse

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31
Q

Define

Quinolones

A

a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the compound 4-quinolone

How well did you know this?
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32
Q

Define

Resistome

A

a proposed expression by Gerard D. Wright for the collection of all the antibiotic resistance genes and their precursors in both pathogenic and non-pathogenic bacteria

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33
Q

Define

Reverse pharmacology

A

the science of integrating documented clinical/experiential hits, into leads by transdisciplinary exploratory studies and further developing these into drug candidates by experimental and clinical research

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34
Q

Define

Rifamycins

A

a natural antibiotic produced by Streptomyces mediterranei, it is a commonly used antimycobacterial drug that inhibits prokaryotic DNA-dependent RNA synthesis and protein synthesis; it blocks RNA-polymerase transcription initiation

How well did you know this?
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35
Q

Define

Selective toxicity

A

refers to the ability of the drug to targets sites that are relative specific to the microorganism responsible for infection

How well did you know this?
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36
Q

Define

Sulphonamides

A

a group of man-made (synthetic) medicines that contain the sulfonamide chemical group. They may also be called sulfa drugs

How well did you know this?
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37
Q

Define

Tetracyclines

A

a class of antibiotics that may be used to treat infections caused by susceptible microorganisms such as gram positive and gram negative bacteria, chlamydiae, mycoplasmata, protozoans, or rickettsiae

How well did you know this?
1
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38
Q

Define

Thienamycin

A

one of the most potent naturally produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. It has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes

How well did you know this?
1
Not at all
2
3
4
5
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39
Q

Define

Transglycosylation

A

A mechanism for glycosidic (see GLYCOSIDE) bond formation, particularly during polysaccharide synthesis. Nucleoside phosphate derivatives act as activated donor compounds in which the energies of their glycosidic bonds are partially conserved in the reaction products

How well did you know this?
1
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40
Q

Define

Transpeptidation

A

a chemical reaction (as the reversible conversion of one peptide to another by a protease) in which an amino acid residue or a peptide residue is transferred from one amino compound to another

How well did you know this?
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41
Q

Define

Trimethoprim

A

an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers’ diarrhea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

Define

Vancomycin

A

an antibiotic that when taken by mouth fights bacteria in the intestines. It is used to treat an infection of the intestines caused by Clostridium difficile, which can cause watery or bloody diarrhea

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Definition

occurs when a particular microorganism obtains the ability to resist the activity of an antimicrobial agent to which it was previously susceptible

A

Acquired resistance

How well did you know this?
1
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3
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44
Q

Definition

Initialism of absorption, distribution, metabolism, excretion, toxicity: A set of test categories used together in drug discovery to provide insight into how a pharmaceutical drug interacts with the body as a whole

A

ADMET

How well did you know this?
1
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3
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45
Q

Definition

any of a group of antibiotics (as streptomycin and neomycin) that inhibit bacterial protein synthesis and are active especially against gram-negative bacteria

A

Aminoglycosides

How well did you know this?
1
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3
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46
Q

Definition

A general term for drugs, chemicals, or other substances that either kill or slow the growth of microbes

A

Antimicrobial agents

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47
Q

Definition

an agent that kills bacteria

A

Bactericidal

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48
Q

Definition

an agent that prevents the growth of bacteria

A

Bacteriostatic

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49
Q

Definition

enzymes produced by bacteria that provide multi-resistance to β-lactam antibiotics such as penicillins, cephalosporins, cephamycins, and carbapenems (ertapenem),

A

β-lactamases

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50
Q

Definition

a class of antibiotic consisting of all antibiotic agents that contain a beta-lactam ring in their molecular structures. This includes penicillin derivatives (penams), cephalosporins (cephems), monobactams, carbapenems and carbacephems

A

β-lactams

How well did you know this?
1
Not at all
2
3
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51
Q

Definition

a large group of antibiotics derived from the mold Acremonium. They are bactericidal (kill bacteria) and work in a similar way to penicillins

A

Cephalosporins

How well did you know this?
1
Not at all
2
3
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5
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52
Q

Definition

an antibiotic produced by certain strains of the bacteria Paenibacillus polymyxa. It is effective against most Gram-negative bacilli

A

Colistin

How well did you know this?
1
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53
Q

Definition

an oral macrolide antibiotic labeled for the treatment of Clostridium difficile–associated diarrhea in adults

A

Fidaxomicin

How well did you know this?
1
Not at all
2
3
4
5
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54
Q

Definition

any of a group of fluorinated derivatives (such as ciprofloxacin and levofloxacin) of quinolone that are used as antibacterial drugs

A

Fluoroquinolones

How well did you know this?
1
Not at all
2
3
4
5
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55
Q

Definition

the traditional approach to discovering new drugs. Typically, a library of chemical compounds is screened for causing a desired phenotype in cells / tissue

A

Forward pharmacology

How well did you know this?
1
Not at all
2
3
4
5
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56
Q

Definition

recent scientific methods relevant to the field of chemistry and biology, in which hundreds of thousands of experimental samples are subjected to simultaneous testing under given conditions

A

High-throughput screening

How well did you know this?
1
Not at all
2
3
4
5
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57
Q

Definition

a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds

A

Hit to lead

How well did you know this?
1
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3
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5
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58
Q

Definition

the movement of genetic material between unicellular and/or multicellular organisms other than by the (“vertical”) transmission of DNA from parent to offspring (reproduction)

A

Horizontal Gene Transfer (HGT)

How well did you know this?
1
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2
3
4
5
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59
Q

Definition

Producing and screening drug candidates on a computer or via computer simulation

A

In silico screening

How well did you know this?
1
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3
4
5
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60
Q

Definition

a natural insensitivity in bacteria that have never been susceptible to a particular antibiotic

A

Intrinsic resistance

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1
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61
Q

Definition

a group of emerging highly drug-resistant Gram-negative bacilli causing infections associated with significant morbidity and mortality

A

Klebsiella pneumoniae carbapenemase (KPC)

How well did you know this?
1
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2
3
4
5
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62
Q

Definition

the process by which a drug candidate is designed after an initial lead compound is identified

A

Lead optimisation

How well did you know this?
1
Not at all
2
3
4
5
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63
Q

Definition

a class of antibiotic that includes erythromycin, roxithromycin, azithromycin and clarithromycin. They are useful in treating respiratory, skin, soft tissue, sexually transmitted, H. pylori and atypical mycobacterial infections

A

Macrolides

How well did you know this?
1
Not at all
2
3
4
5
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64
Q

Definition

a gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections

A

Mobilised colistin resistance (MCR)

How well did you know this?
1
Not at all
2
3
4
5
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65
Q

Definition

an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections

A

New Dehli metallo-β-lactamase

How well did you know this?
1
Not at all
2
3
4
5
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66
Q

Definition

infections that have been caught in a hospital and are potentially caused by organisms that are resistant to antibiotics

A

Nosocomial infections

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67
Q

Definition

a protein involved in signal transduction. It is a highly expressed, cytoplasmic protein found in mature olfactory sensory receptor neurons of all vertebrates

A

Omp protein

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1
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3
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5
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68
Q

Definition

a novel class of synthetic antimicrobial agents unrelated to any other antibacterial drug class. They were originally developed as monoamine oxidase inhibitors for treatment of depression, with subsequent recognition of their antimicrobial properties

A

Oxazolidinones

How well did you know this?
1
Not at all
2
3
4
5
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69
Q

Definition

an antibiotic or group of antibiotics produced naturally by certain blue molds, and now usually prepared synthetically

A

Penicillin

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70
Q

Definition

what the drug does to the body

A

Pharmacodynamics

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71
Q

Definition

what the body does to the drug

A

Pharmacokinetics

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72
Q

Definition

beta barrel proteins that cross a cellular membrane and act as a pore, through which molecules can diffuse

A

Porin protein

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73
Q

Definition

a member of a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the compound 4-quinolone

A

Quinolones

How well did you know this?
1
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2
3
4
5
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74
Q

Definition

a proposed expression by Gerard D. Wright for the collection of all the antibiotic resistance genes and their precursors in both pathogenic and non-pathogenic bacteria

A

Resistome

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75
Q

Definition

the science of integrating documented clinical/experiential hits, into leads by transdisciplinary exploratory studies and further developing these into drug candidates by experimental and clinical research

A

Reverse pharmacology

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76
Q

Definition

a natural antibiotic produced by Streptomyces mediterranei, it is a commonly used antimycobacterial drug that inhibits prokaryotic DNA-dependent RNA synthesis and protein synthesis; it blocks RNA-polymerase transcription initiation

A

Rifamycins

How well did you know this?
1
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2
3
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77
Q

Definition

refers to the ability of the drug to targets sites that are relative specific to the microorganism responsible for infection

A

Selective toxicity

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1
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3
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78
Q

Definition

a group of man-made (synthetic) medicines that contain the sulfonamide chemical group. They may also be called sulfa drugs

A

Sulphonamides

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79
Q

Definition

a class of antibiotics that may be used to treat infections caused by susceptible microorganisms such as gram positive and gram negative bacteria, chlamydiae, mycoplasmata, protozoans, or rickettsiae

A

Tetracyclines

How well did you know this?
1
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80
Q

Definition

one of the most potent naturally produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. It has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes

A

Thienamycin

How well did you know this?
1
Not at all
2
3
4
5
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81
Q

Definition

A mechanism for glycosidic (see GLYCOSIDE) bond formation, particularly during polysaccharide synthesis. Nucleoside phosphate derivatives act as activated donor compounds in which the energies of their glycosidic bonds are partially conserved in the reaction products

A

Transglycosylation

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82
Q

Definition

a chemical reaction (as the reversible conversion of one peptide to another by a protease) in which an amino acid residue or a peptide residue is transferred from one amino compound to another

A

Transpeptidation

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83
Q

Definition

an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers’ diarrhea

A

Trimethoprim

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84
Q

Definition

an antibiotic that when taken by mouth fights bacteria in the intestines. It is used to treat an infection of the intestines caused by Clostridium difficile, which can cause watery or bloody diarrhea

A

Vancomycin

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85
Q

What are some examples of natural antimicrobial agents?

A

Penicillin

Aminoglycosides

Polyenes

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86
Q

What are some examples of semisynthetic antimicrobial agents?

A

β-lactams

Cephalosporins

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87
Q

What are some examples of synthetic antimicrobial agents?

A

Oxazolidinones

Quinolones

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88
Q

What is the mode of action of antibiotics?

A

Disruption of cell membrane funciton

Inhibition of cell wall synthesis

Inhibition of RNA and DNA synthesis

Inhibition of folic acid metabolism

Inhibition of protein sythesis

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89
Q

What is the basic monomer of peptidoglycan

A

A peptapeptide with D-ala D-ala at the end of the stem

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90
Q

What do Penicillin-Binding proteins (PBPs) do?

A

PBPs play multiple roles in cell wall synthesis and maintenance of peptidoglycan:

  • transglycosylation (wall synthesis for growth and septation)
  • transpeptidation (crosslinking and remodelling)
  • peptide cleavage (D-Ala carboxypeptidases, endopeptidases)
    • control of crosslinking, insertion of new strands
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91
Q

What is a critical part in the action of PBPs? What happens when you interupt it?

A

A critical part of these processes is the recognition of the D-Ala-D-Ala sequence of the MurNac-GlcNac pentapeptide. Interfering with this recognition disrupts the cell wall synthesis

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92
Q

How do β-lactams act as antibiotics (general idea)?

A

The β-lactam ring mimics the structure of the D-Ala-D-Ala link and bind to the same place in the PBPs (the active site), disrupting the crosslinking process.

β-lactams inactivate PBPs.

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93
Q

β-lactams are bacteriocidal/bacteriostatic

A

β-lactams are bacteriocidal

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94
Q

How does resistance to β-lactams occur?

A

Resistance occurs through production of β-lactamases or PBP and porin mutations

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95
Q

How do glycopeptide antibiotics, like Vancomycin, work?

A

Bind to the terminal D-Ala-D-Ala dipeptide inhibiting transglycosylation and transpeptidation of peptidoglycan.

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96
Q

Which antibiotics interfere with cell wall biosynthesis?

A

β-lactams

Vancomycin

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97
Q

What antibiotics inhibit protein synthesis?

A

Tetracyclines

Aminoglycosides

Macrolides

Oxazolidinones

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98
Q

Why can molecules that target bacterial ribosomes be used as antibiotics?

A

Selective toxicity due to differences in bacterial/eukaryotic ribosomes

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99
Q

What are examples of antibiotics that target the 30S subunit?

A

Aminoglycosides

Tetracyclines

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100
Q

What are examples of antibiotics that target the 50S subunit?

A

Macrolides

Oxazolidinones

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101
Q

How do tetracyclines function?

A

Bind to the 30S ribosomal subunit preventing entry of amino acyl-tRNA into the A-site

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102
Q

How does resistance to tetracyclines occur?

A

Resistance through efflux or ribosomal protection proteins

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103
Q

How do aminoglycosides funtion?

A

Interfere with proof-reading process for incoming aa-tRNA • Results in premature termination or proteins with amino acid substitutions

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104
Q

How does resistance to aminoglycosides occur?

A

Resistance through target mutations and modifying enzymes

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105
Q

How do macrolides function?

A

Bind reversibly to 23S rRNA in 50S subunit (peptidyl transferase domain)

Disrupt movement of tRNA from A site to P site thereby inhibiting peptide chain elongation.

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106
Q

How does resistance to macrolides occur?

A

Multiple resistance mechanisms

  • Target modification (e.g., RNA methylation)
  • Efflux
  • Enzymatic modification
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107
Q

How do Oxazolidinones function?

A

Bind to rRNA on the A side of the peptidyltransferase center (PTC) of the ribosome

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108
Q

How does resistance to Oxazolidinones occur?

A

Resistance mediated through rRNA mutations

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109
Q

Which antibiotics act as inibitors of nucleic acid synthesis?

A

Fluoroquinolones

Rifamycins

Fidaxomicin

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110
Q

How do Fluoroquinolones function?

A

Bind to DNA gyrase and topoisomerases blocking formation of complex with nicked DNA

Blockage of DNA replication and DNA repair

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111
Q

How does resistance to Fluoroquinolones develop

A

Resistance through gyrA and gyrB mutations and through expression of gyrase-binding proteins

112
Q

How do Rifamycins and Fidaxomicin function?

A

Bind to DNA-dependent RNA polymerase and block synthesis of mRNA

113
Q

What are metabolic antagonists?

A

Antimicrobials that inhibit or block metabolic pathways

114
Q

What are examples of metabolic antagonists?

A

Sulphonamides

Trimethoprim

115
Q

Why are metabolic antagonists that target folic acid selective for bacteria and not human cells?

A

Selective because humans obtain folic acid from diet and human dihydrofolate reductase is relatively resistant to trimethoprim.

116
Q

How do bacteria become resistant to antimicrobials?

A

Chromosomally-mediated resistance

Plasmid-mediated resistance

Plasmid-mediated resistance on a transposon

117
Q

What does chromosomally-mediated resistance produce?

A

Chromosomal mutation can produce a drug-resistant target, which confers resistance on the bacterial cell and allows it to multiply in the presence of antibiotic.

118
Q

How does plasmid-mediated resistance work?

A

Resistance genes carried on plasmids can spread from one cell to another more rapidly than cells themselves divide and spread

119
Q

How does plasmid-mediated resistance on a transposon work?

A

Resistance genes on transposable genetic elements move between plasmids and the chromosome and from one plasmid to another, thereby allowing greater dissemination of the resistance gene.

120
Q

What are the features of acquired resistance by mutation?

A
  • Usually result in resistance to a single class of antibiotics
  • Generally alters the antimicrobial target site, a modifying enzyme or an efflux system
  • Cross-resistance to structurally related compounds only
121
Q

In what ways do bacteria modify the antibiotic molecule?

A
  1. Inactivate the drug by chemically cleaving it
  2. Inactivate the drug by adding chemical moieties.
122
Q

How do β-lactamases confer resistance?

A

Inactivate the drug by chemically cleaving it

123
Q

How do aminoglycoside modifying enzymes confer resistance?

A

Inactivate the drug by adding chemical moieties.

124
Q

In what ways can modified antibiotic transport confer resistance?

A

Decreased cell wall pemeability

Increased efflux from the cell

125
Q

How does decreased cell wall permeability prevent the action of some antibiotics?

A

Altered porin or Omp proteins lead to decreased uptake of βlactam antibiotics in Klebsiella pneumoniae and Pseudomonas aeruginosa.

126
Q

How does modification of the target site confer resistance?

A

Alteration of the target site to reduce susceptibility to antibiotic

Acquisition of genes encoding enzymes that alter target

127
Q

What does Vancomycin resistance involve?

A

Vancomycin resistance involves acquisition of genes encoding enzymes that alter the D-Ala-D-Ala to D-Ala-D-Lac, reducing the binding of the vancomycin drug.

128
Q

How do we treat patients with resistant Gram-negative infections?

A

The β-lactams were the ‘golden bullet’ for a long time for infections with Gram-negative pathogens

Other current options for treatment include

  • Tigecycline (tetracycline derivative)
  • Colistin (also known as polymyxin E)

Not well suited to serious infections (poor pharmacokinetic profiles)

  • Polymixins have side effects including kidney and neurotoxicity
  • Tetracyclines have gastrointestinal side effect
129
Q
A

Efflux pump mechanism

130
Q

Aminoglycoside-modifying enzymes act to change the chemical structure of the aminoglycoside, preventing it from binding to its target.

Select one:

True

False

A

Aminoglycoside-modifying enzymes act to change the chemical structure of the aminoglycoside, preventing it from binding to its target.

Select one:

True

False

131
Q

The major role of penicillin-binding proteins in bacterial cells is to

Select one:

a. bind penicillin and thereby confer penicillin resistance.
b. crosslink peptidoglycan strands by catalyzing transpeptidation.
c. bind penicillin and thereby block protein biosynthesis.
d. act as an essential co-factor in protein biosynthesis.

A

The major role of penicillin-binding proteins in bacterial cells is to

Select one:

a. bind penicillin and thereby confer penicillin resistance.

b. crosslink peptidoglycan strands by catalyzing transpeptidation.

c. bind penicillin and thereby block protein biosynthesis.
d. act as an essential co-factor in protein biosynthesis.

132
Q

The structure below is a cell wall from which microorganism?

A

Fungus

133
Q

Beta-lactamases are a diverse set of enzymes that can inactivate many different types of beta-lactam antibiotics.

Select one:

True

False

A

Beta-lactamases are a diverse set of enzymes that can inactivate many different types of beta-lactam antibiotics.

Select one:

True

False

134
Q

Which of the following is the major reason why it has been difficult to treat viral infections with chemotherapeutic agents?

Select one:

a. Viral metabolism resembles that of their hosts so there is no selective point of attack.
b. Viruses use the metabolic machinery of their hosts, which limits many of the potential points of attack.
c. Viruses have no metabolism and therefore offer no selective point of attack.
d. Actually, viruses are not difficult to treat with chemotherapeutic agents.

A

Which of the following is the major reason why it has been difficult to treat viral infections with chemotherapeutic agents?

Select one:

a. Viral metabolism resembles that of their hosts so there is no selective point of attack.

b. Viruses use the metabolic machinery of their hosts, which limits many of the potential points of attack.

c. Viruses have no metabolism and therefore offer no selective point of attack.
d. Actually, viruses are not difficult to treat with chemotherapeutic agents.

135
Q

A single mutation to a gene can be enough to induce resistance.

Select one:

True

False

A

A single mutation to a gene can be enough to induce resistance.

Select one:

True

False

136
Q

Peptidoglycan synthesis inhibitors often induce bacterial lysis, while protein synthesis inhibitors do not. Beta-lactam antibiotics (e.g. penicillin, cefoxitin) cause bacterial lysis because:

Select one:

a. They block the ribosomal exit tunnel
b. They disrupt cell wall biosynthesis
c. They induce DNA breaks
d. They induce the synthesis of aberrant proteins

A

Peptidoglycan synthesis inhibitors often induce bacterial lysis, while protein synthesis inhibitors do not. Beta-lactam antibiotics (e.g. penicillin, cefoxitin) cause bacterial lysis because:

Select one:

a. They block the ribosomal exit tunnel

b. They disrupt cell wall biosynthesis

c. They induce DNA breaks
d. They induce the synthesis of aberrant proteins

137
Q

The mechanisms that resistant bacteria can use to generate a resistant phenotype include

Select one:

a. Modification of the drug target, drug transport or drug itself
b. The acquisition of resistance genes
c. Horizontal gene transfer of plasmids containing transposons.
d. Spontaneous mutation of the chromosome

A

The mechanisms that resistant bacteria can use to generate a resistant phenotype include

Select one:

a. Modification of the drug target, drug transport or drug itself

b. The acquisition of resistance genes
c. Horizontal gene transfer of plasmids containing transposons.
d. Spontaneous mutation of the chromosome

138
Q

HOW DO I MEDIATE RESISTANCE? I alter the sequence of the D-Ala-D-Ala sequence of the MurNac-GlcNac pentapeptide to D-Ala-D-Lac?

A

Alteration of the antibiotic target. Vancomycin resistance is mediated by the acquisition of genes that encode enzymes that change the target of vancomycin (D-Ala-D-Ala of the starting pentapeptide of peptidoglycan). This reduces the ability of vancomycin to bind and act.

139
Q

Which of the following is a desirable general characteristic of antimicrobial drugs?

Select one:

a. Selective toxicity
b. Broad-spectrum of activity
c. Bactericidal rather than bacteriostatic
d. All of the choices are correct.

A

Which of the following is a desirable general characteristic of antimicrobial drugs?

Select one:

a. Selective toxicity
b. Broad-spectrum of activity
c. Bactericidal rather than bacteriostatic

d. All of the choices are correct.

140
Q

The blaKPC gene encodes resistance to carbapenems.

Select one:

True

False

A

The blaKPC gene encodes resistance to carbapenems.

Select one:

True

False

141
Q

MCR-1 refers to the protein the encodes resistance to the polymyxins.

Select one:

True

False

A

MCR-1 refers to the protein the encodes resistance to the polymyxins.

Select one:

True

False

142
Q

As long as the antibiotic can get inside the bacteria (through the cell wall and membrane), it will be active.

Select one:

True

False

A

As long as the antibiotic can get inside the bacteria (through the cell wall and membrane), it will be active.

Select one:

True

False

143
Q

Which of the following is likely to have the most toxic side effects to humans?

Select one:

a. Inhibitors of cell wall synthesis
b. Inhibitors of protein synthesis
c. Disrupters of cell membrane structure
d. Inhibitors of DNA synthesis

A

Which of the following is likely to have the most toxic side effects to humans?

Select one:

a. Inhibitors of cell wall synthesis
b. Inhibitors of protein synthesis

c. Disrupters of cell membrane structure

d. Inhibitors of DNA synthesis

144
Q

If you come into contact with a multi-drug resistant bacteria, you will probably die.

Select one:

True

False

A

If you come into contact with a multi-drug resistant bacteria, you will probably die.

Select one:

True

False

145
Q

Transposable genetic elements can move between plasmids and chromosomes and from one plasmid to another, thereby allowing greater dissemination of the resistance gene?

Select one:

True

False

A

Transposable genetic elements can move between plasmids and chromosomes and from one plasmid to another, thereby allowing greater dissemination of the resistance gene?

Select one:

True

False

146
Q

Protein synthesis inhibitors generally do not result in bacterial lysis, while peptidoglycan synthesis inhibitors do. Aminoglycoside antibiotics (e.g. Streptomycin, Kanamycin) cause bacterial death because:

Select one:

a. They block the ribosomal exit tunnel
b. They disrupt cell wall biosynthesis
c. The induce DNA breaks
d. The induce the synthesis of aberrant proteins

A

Protein synthesis inhibitors generally do not result in bacterial lysis, while peptidoglycan synthesis inhibitors do. Aminoglycoside antibiotics (e.g. Streptomycin, Kanamycin) cause bacterial death because:

Select one:

a. They block the ribosomal exit tunnel
b. They disrupt cell wall biosynthesis
c. The induce DNA breaks

d. The induce the synthesis of aberrant proteins

147
Q

Generally, a bacterium only has one resistance mechanism per antibiotic.

Select one:

True

False

A

Generally, a bacterium only has one resistance mechanism per antibiotic.

Select one:

True

False

148
Q

Resistance by mutation is a rare event and therefore is not a concern for antibiotic resistance.

Select one:

True

False

A

Resistance by mutation is a rare event and therefore is not a concern for antibiotic resistance.

Select one:

True

False

149
Q

WHO AM I? I am a major cause for concern for Gram negative pathogens. I am an enzyme and can cleave the beta-lactam ring in beta-lactam antibiotics. I have lots of friends and family spread around the world. I can be found in the chromosome, on plasmids and transposons. There are over 1000 different classes of me.

A

beta-lactamases

150
Q

Bacteria only become drug resistant due to incorrect usage of antibiotics?

Select one:

True

False

A

Bacteria only become drug resistant due to incorrect usage of antibiotics?

Select one:

True

False

151
Q

WHO AM I? I am a resistance-mediating enzyme. I alter the target binding site of the macrolide antibiotics by methylating a residue in the 23S RNA of the 50S ribosomal subunit. There are at least 30 different classes of me.

A

The erythromycin ribosomal mediating (Erm) enzyme

152
Q

What is a hit?

A

A “hit” candidate is an active substance that has the desired antimicrobial action on the microbe or in a disease model.

153
Q

Where do you find hits?

A

Start with the natural substrate and produce a derivative.

Screening libraries (‘000s to 000’000s of candidates)

154
Q

How do you identify a “hit” in a library?

A

1) High-throughput screening
2) Medium throughput screening
3) In silico (computational) screening

155
Q

What are the advantages of High-throughput screening?

A
  • Automated (high speed + low running cost)
  • Small volumes (less reagents = cheaper)
  • Screen millions of compounds if desired
  • Broad applicability (can do many different types of assays)
156
Q

What are the disadvantages of High-throughput screening?

A
  • Expensive infrastructure
  • Can be difficult to optimize (translation of complex assays from lab to a robot set-up can be hard to achieve)
  • Can have high rate of false positives
157
Q

What are the advantages of Medium throughput screening?

A
  • Semi-automated (speed + low running cost)
  • Cheaper set up (can be laboratory-based)
  • Broader applicability (can do many different types of assays)
  • Can get more data from single assay
  • Less false positives
158
Q

What are the disadvantages of Medium throughput screening?

A
  • Limited number of samples
  • Larger volumes (more regents required)
159
Q

What are the advantages of In silico (computational) screening?

A
  • Cost
  • Speed
  • (Apparent) higher hit rate
160
Q

What are the disadvantages of In silico (computational) screening?

A
  • Requires drug target is known and extensively characterised (structure & mechanism)
  • In reality, false positive ‘hits’ are very high
  • Requires a very high level of understanding of protein chemistry
  • Must be experimentally validated
161
Q

What do you do once a hit candidate has been identified?

A
  • Identify the active substance / chemical composition of the “hit”.
  • In vitro production or commercial supply of hit.
  • Re-test hit in a dose-response assay and confirm activity.
162
Q

What is the focus of hit to lead optimisation?

A

The focus of the hit to lead optimisation is:

  1. Solubility of the candidate.
  2. ADMET (Adsorption, Disposition, Metabolism, Excretion and Toxicity).
  3. Ensuring minimal or no ‘off-target effects’.
163
Q

What is drug design?

Select one:

a. The inventive process of finding new medicines.
b. The process by which existing drugs are improved.
c. The process by which all antimicrobials are made.
d. The process of finding active pharmaceutical compounds by trial and error.

A

What is drug design?

Select one:

a. The inventive process of finding new medicines.

b. The process by which existing drugs are improved.
c. The process by which all antimicrobials are made.
d. The process of finding active pharmaceutical compounds by trial and error.

164
Q

X-ray crystal structures can

Select one:

a. Slow the drug discovery process because crystal structures are hard and slow to finish.
b. Speed up the process of hit candidate optimisation by improving structure-activity relationships.
c. Speed up the process of lead candidate optimisation by improving drug-like properties.
d. Stop a drug discovery project if a crystal structure cannot be determined.

A

X-ray crystal structures can

Select one:

a. Slow the drug discovery process because crystal structures are hard and slow to finish.

b. Speed up the process of hit candidate optimisation by improving structure-activity relationships.

c. Speed up the process of lead candidate optimisation by improving drug-like properties.
d. Stop a drug discovery project if a crystal structure cannot be determined.

165
Q

The aim of hit-to-lead optimisation is

Select one:

a. To find an active substance that has desired anti-microbial action.
b. To optimise an active substance to be more potent.
c. To improve the potency of an active substance.
d. To optimise an active substance to retain potency and have desirable drug-like properties.

A

The aim of hit-to-lead optimisation is

Select one:

a. To find an active substance that has desired anti-microbial action.
b. To optimise an active substance to be more potent.
c. To improve the potency of an active substance.

d. To optimise an active substance to retain potency and have desirable drug-like properties.

166
Q

Which of the following best describe the scientific disciplines required for early antimicrobial drug discovery?

Select one:

a. Microbiology / biochemistry, chemistry / medicinal chemistry, structural biology.
b. Microbiology, chemistry, bioinformatics, structural biology.
c. Chemistry / medicinal chemistry, structural biology.
d. Biochemistry and Pharmacology.

A

Which of the following best describe the scientific disciplines required for early antimicrobial drug discovery?

Select one:

a. Microbiology / biochemistry, chemistry / medicinal chemistry, structural biology.

b. Microbiology, chemistry, bioinformatics, structural biology.
c. Chemistry / medicinal chemistry, structural biology.
d. Biochemistry and Pharmacology.

167
Q

What are the essential requirements starting a new drug discovery project with a drug target

Select one:

a. A complete understanding of the role of the target within the microbe physiology.
b. Target identification, in vitro production and a robust assay to assess the target activity.
c. Target identification, the mechanism of action and the structure of the target.
d. Target identification, the mechanism of action and a robust assay to assess the target activity.

A

What are the essential requirements starting a new drug discovery project with a drug target

Select one:

a. A complete understanding of the role of the target within the microbe physiology.

b. Target identification, in vitro production and a robust assay to assess the target activity.

c. Target identification, the mechanism of action and the structure of the target.
d. Target identification, the mechanism of action and a robust assay to assess the target activity.

168
Q

TRUE OR FALSE? One Health refers to the collaborative effort of multiple disciplines – working locally, nationally and globally – to attain optimal health for people, animals and the environment.

Select one:

True

False

A

TRUE OR FALSE? One Health refers to the collaborative effort of multiple disciplines – working locally, nationally and globally – to attain optimal health for people, animals and the environment.

Select one:

True

False

169
Q

TRUE or FALSE? Antibiotic use in animal husbandry represents one of the greatest challenges for antibiotic control and stewardship.

Select one:

True

False

A

TRUE or FALSE? Antibiotic use in animal husbandry represents one of the greatest challenges for antibiotic control and stewardship.

Select one:

True

False

170
Q

TRUE or FALSE? Treating cancer patients will become more difficult in the absence of effective antibiotics.

Select one:

True

False

A

TRUE or FALSE? Treating cancer patients will become more difficult in the absence of effective antibiotics.

Select one:

True

False

171
Q

TRUE or FALSE? Rapid and accurate, point of care, diagnostics are vital to control ‘superbugs’.

Select one:

True

False

A

TRUE or FALSE? Rapid and accurate, point of care, diagnostics are vital to control ‘superbugs’.

Select one:

True

False

172
Q

TRUE or FALSE? Education is an essential part of antibiotic stewardship.

Select one:

True

False

A

TRUE or FALSE? Education is an essential part of antibiotic stewardship.

Select one:

True

False

173
Q

The animal microbiome can (select all correct answers)

Select one or more:

a. exchange with farm workers who can then exchange with their friends, family and co-workers.
b. can be readily exchanged by eating animal meat
c. can contaminate vegetables
d. can acquire resistance genes from soil microbiome
e. only acquires resistance from over-use of antibiotics
f. can only effect other animals

A

The animal microbiome can (select all correct answers)

Select one or more:

a. exchange with farm workers who can then exchange with their friends, family and co-workers.

b. can be readily exchanged by eating animal meat

c. can contaminate vegetables

d. can acquire resistance genes from soil microbiome

e. only acquires resistance from over-use of antibiotics
f. can only effect other animals

174
Q

The advantages of high-throughput screening for drug discovery are that the process is

Select one:

a. fully automated, accepts different assay types and can screen millions of compounds.
b. semi-automated, accepts different assay types and can screen thousands of compounds.
c. semi-automated and the screening is performed on computers
d. fully automated, accepts different assay types and has a low rate of false positives hits.

A

The advantages of high-throughput screening for drug discovery are that the process is

Select one:

a. fully automated, accepts different assay types and can screen millions of compounds.

b. semi-automated, accepts different assay types and can screen thousands of compounds.
c. semi-automated and the screening is performed on computers
d. fully automated, accepts different assay types and has a low rate of false positives hits.

175
Q

Define

Acellular vaccines

A

A vaccine that may contain cellular material but does not contain complete cells

176
Q

Define

Acquired immunity

A

Immunity acquired by infection or vaccination (active immunity) or by the transfer of antibody or lymphocytes from an immune donor (passive immunity)

177
Q

Define

Active immunity

A

the immunity which results from the production of antibodies by the immune system in response to the presence of an antigen

178
Q

Define

Adjuvant

A

a substance which enhances the body’s immune response to an antigen.

179
Q

Define

Alum

A

the classical adjuvant most often used in vaccines in humans, includes a range of salts of aluminum precipitated under basic conditions, usually aluminum sulfate mixed with sodium or potassium hydroxide plus a variable amount of phosphate.

180
Q

Define

Antigen

A

a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies

181
Q

Define

Damage associated molecular patterns (DAMPs)

A

molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response

182
Q

Define

DTaP

A

a vaccine that helps children younger than age 7 develop immunity to three deadly diseases caused by bacteria: diphtheria, tetanus, and whooping cough (pertussis)

183
Q

Define

DTwP

A

a mixture of the detoxified toxins (toxoids) of diphtheria and tetanus and inactivated Bordetella pertussis that have been adsorbed onto an aluminum salt

184
Q

Define

Efficacy

A

the percentage reduction of disease in a vaccinated group of people compared to an unvaccinated group, using the most favorable conditions

185
Q

Define

Herd immunity

A

a form of indirect protection from infectious disease that occurs when a large percentage of a population has become immune to an infection, thereby providing a measure of protection for individuals who are not immune

186
Q

Define

Killed inactivate vaccines

A

a vaccine consisting of virus particles, bacteria, or other pathogens that have been grown in culture and then lose disease producing capacity

187
Q

Define

Live attenuated vaccines

A

a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or “live”)

188
Q

Define

Measles

A

a highly contagious infectious disease caused by the measles virus

189
Q

Define

Nanopatches

A

a needle-free vaccine delivery device

190
Q

Define

Opsonise

A

make (a foreign cell) more susceptible to phagocytosis

191
Q

Define

Passive immunity

A

the short-term immunity which results from the introduction of antibodies from another person or animal

192
Q

Define

Recombinant vaccines

A

a vaccine produced through recombinant DNA technology

193
Q

Define

Reservoir

A

is the population of organisms or the specific environment in which an infectious pathogen naturally lives and reproduces, or upon which the pathogen primarily depends for its survival

194
Q

Define

Subunit vaccines

A

a fragment of a pathogen, typically a surface protein, that is used to trigger an immune response and stimulate acquired immunity against the pathogen from which it is derived

195
Q

Define

The Cutter Incident

A

one of the worst pharmaceutical disasters in US history, and exposed several thousand children to live polio virus on vaccination

196
Q

Define

Toxoid vaccines

A

A vaccine made from a toxin (poison) that has been made harmless but that elicits an immune response against the toxin

197
Q

Define

Tropism

A

the turning of all or part of an organism in a particular direction in response to an external stimulus

198
Q

Define

Variolation

A

the method first used to immunize an individual against smallpox (Variola) with material taken from a patient or a recently variolated individual, in the hope that a mild, but protective, infection would result

199
Q

Definition

A vaccine that may contain cellular material but does not contain complete cells

A

Acellular vaccines

200
Q

Definition

Immunity acquired by infection or vaccination (active immunity) or by the transfer of antibody or lymphocytes from an immune donor (passive immunity)

A

Acquired immunity

201
Q

Definition

the immunity which results from the production of antibodies by the immune system in response to the presence of an antigen

A

Active immunity

202
Q

Definition

a substance which enhances the body’s immune response to an antigen.

A

Adjuvant

203
Q

Definition

the classical adjuvant most often used in vaccines in humans, includes a range of salts of aluminum precipitated under basic conditions, usually aluminum sulfate mixed with sodium or potassium hydroxide plus a variable amount of phosphate.

A

Alum

204
Q

Definition

a toxin or other foreign substance which induces an immune response in the body, especially the production of antibodies

A

Antigen

205
Q

Definition

molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response

A

Damage associated molecular patterns (DAMPs)

206
Q

Definition

a vaccine that helps children younger than age 7 develop immunity to three deadly diseases caused by bacteria: diphtheria, tetanus, and whooping cough (pertussis)

A

DTaP

207
Q

Definition

a mixture of the detoxified toxins (toxoids) of diphtheria and tetanus and inactivated Bordetella pertussis that have been adsorbed onto an aluminum salt

A

DTwP

208
Q

Definition

the percentage reduction of disease in a vaccinated group of people compared to an unvaccinated group, using the most favorable conditions

A

Efficacy

209
Q

Definition

a form of indirect protection from infectious disease that occurs when a large percentage of a population has become immune to an infection, thereby providing a measure of protection for individuals who are not immune

A

Herd immunity

210
Q

Definition

a vaccine consisting of virus particles, bacteria, or other pathogens that have been grown in culture and then lose disease producing capacity

A

Killed inactivate vaccines

211
Q

Definition

a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or “live”)

A

Live attenuated vaccines

212
Q

Definition

a highly contagious infectious disease caused by the measles virus

A

Measles

213
Q

Definition

a needle-free vaccine delivery device

A

Nanopatches

214
Q

Definition

make (a foreign cell) more susceptible to phagocytosis

A

Opsonise

215
Q

Definition

the short-term immunity which results from the introduction of antibodies from another person or animal

A

Passive immunity

216
Q

Definition

a vaccine produced through recombinant DNA technology

A

Recombinant vaccines

217
Q

Definition

is the population of organisms or the specific environment in which an infectious pathogen naturally lives and reproduces, or upon which the pathogen primarily depends for its survival

A

Reservoir

218
Q

Definition

a fragment of a pathogen, typically a surface protein, that is used to trigger an immune response and stimulate acquired immunity against the pathogen from which it is derived

A

Subunit vaccines

219
Q

Definition

one of the worst pharmaceutical disasters in US history, and exposed several thousand children to live polio virus on vaccination

A

The Cutter Incident

220
Q

Definition

A vaccine made from a toxin (poison) that has been made harmless but that elicits an immune response against the toxin

A

Toxoid vaccines

221
Q

Definition

the turning of all or part of an organism in a particular direction in response to an external stimulus

A

Tropism

222
Q

Definition

the method first used to immunize an individual against smallpox (Variola) with material taken from a patient or a recently variolated individual, in the hope that a mild, but protective, infection would result

A

Variolation

223
Q

What is the first main barrier to infectious agents?

A

Skin

224
Q

Which three main types of leukocytes are there?

A

Lymphocytes

APCs

Innate cells (NK, neutrophils etc.)

225
Q

What does immunological memory require?

A

Innate immune responses

Antigen uptake and presentation to trigger

Adaptive immune responses (B and T cells)

226
Q

What does vaccination and immunological memory do to the number of B or T cells that recognise a specific antigen?

A

Increases the number of B or T cells that recognise a specific antigen

227
Q

What does vaccination and immunological memory do to the amount of signal needed to activate antigen-specific memory B and T cells?

A

Decreases the amount of signal needed to activate antigen-specific memory B and T cells

228
Q

What are the two types of acquired immunity?

A

Active and Passive

229
Q

What is passive immunisation good for?

A
  • Toxins: snake bites, tetanus, rabies, gas gangrene
  • Outbreaks where antibody can provide protection to survivors but vaccines are not developed
230
Q

Passive immunisation is ideally given before/after infection

A

Passive immunisation is ideally given before​ infection

231
Q

Passive immunisation provides delayed/immediate onset of protection

A

Passive immunisation provides immediate ​onset of protection

232
Q

Passive immunisation is long-lasting/limited

A

Passive immunisation is limited

233
Q

Active immunisation is ideally given before/after infection

A

Active immunisation is ideally given before infection

234
Q

Active immunisation protection is delayed/immediate

A

Active immunisation protection is delayed

235
Q

What is active immunisation good for?

A
  • Inducing widespread immunity in the community to highly transmissible diseases
  • Influenza, measles, HPV
236
Q

What is the ultimate aim of vaccination? What are the secondary aims?

A

Eradication of disease from population

  • Prevent infection
  • Reduce infectious load/severity
  • Reduce infection transmission
237
Q

What is the major limit of herd immunity?

A

Herd immunity only applies for diseases that spread from human to human

238
Q

___________: a compound that triggers innate immunity

___________: a component of the virus, bacteria or parasite that is immunogenic

A

Adjuvant: a compound that triggers innate immunity

Antigen: a component of the virus, bacteria or parasite that is immunogenic

239
Q

What are the criteria for selecting suitable antigens?

A
  1. Abundantly expressed and accessible to protective immune mechanisms:
    • Expressed on the pathogen surface or a secreted toxin if antibody‐mediated immunity provides protection
    • Expressed on infected cells if T cell‐mediated immunity provides protection
  2. Does not vary:
    • Some pathogens can mutate antigens if immune responses are directed against those antigens (HIV, influenza, etc.)
    • Some pathogens change antigens during their natural lifecycle (malaria, TB, etc.)
    • Therefore, choose an antigen which is essential to critical life stages of the pathogen
240
Q

Why do viruses live HIV-1 ungergo extremely rapid rates of mutation?

A

RNA polymerase doesn’t proofread

241
Q

How do you combat the increadible diversity of HIV in order to make a vaccine?

A
  • Env is the most abundant antigen on the virus surface and it mutates at incredibly high rate
  • BUT certain sites on Env must be conserved to enable virus binding and entry to infect cells‐ the “CD4 binding site”
  • We can make antibodies for the CD4 binding site that neutralise a diverse array of HIV‐1 viruses:
    • Use in passive immunisation We can focus the immune response on the CD4 binding site:
    • Vaccinate with the CD4 binding site alone as our antigen
242
Q

What does a good adjuvant do?

A
  1. Increases the magnitude of the adaptive immune response
  2. Shapes the type of adaptive immune response (antibody isotype, CD4+ T cell subset, CD8+ T cells)
243
Q

How do adjuvants augment the immune response?

A
  1. Trigger innate immunity
  2. Promote uptake of antigen by DCs
244
Q

What are some examples of PRRs that recognise PAMPs and DAMPs?

A

TLR

RLR

CLR

NLR

245
Q

What do PRRs bind to?

A

PAMPs

DAMPs

246
Q

What molecules are usually used as adjuvants?

A

PAMPs or induced DAMPs

247
Q

What do you need to consider about adjuvant that you choose?

A

What branch of the immune system does it fire up

Each PAMP/DAMP elicits a different set of innate cytokines, which acts on B cell and T cells to skew the immune system in distinct directions:

i.e. IL‐12 + IFN‐γ= IgG2a antibody, Th1 CD4 T cells and CD8 T cells

248
Q

Which adjuvant triggers innate immunity and promotes antigen uptake?

A

Alum

249
Q

True or False:

Only one adjuvant can be used per vaccine

A

False

There can be synergy when adjuvants are combined‐ RTS’S (Malaria) and Shingrix (Shingles)

250
Q

What are the three main considerations when designing a vaccine?

A

Route of delivery

Adjuvant

Antigen

251
Q

What are the four phases for the clincial testing of vaccines?

A

Phase I: Safety

Phase II: Immunogenicity (and Safety)

Phase III: Immunogenicity, Feasibility (and Safety)

Phase IV: Post‐approval monitoring (i.e. Safety)

252
Q

What are the potential side-effects of vaccines?

A
  • Swelling at vaccine site, fever, muscle aches, fatigue: activation of innate immunity causes immune cell recruitment and pyrexia, etc
  • Anaphylaxis: some vaccines are cultured in eggs or yeast expression systems (15 min wait after vaccination)
  • Seizures in children: due to vaccine‐induced innate immunity causing fevers. Similar to infection‐induced febrile seizures.
  • Guillian‐Barré syndrome: due to vaccine‐induced innate immunity triggering auto‐immunity. Can also be induced by infections.
253
Q

What are the three types of vaccines?

A

Live attenuated vaccines

Killed inactivated vaccines

Subunit vaccines

254
Q

What does attentuated mean?

A

passage through cell culture or use of genetic techniques to induce mutations that remove virulence but retain immunogenicity

255
Q

How are pathogens killed to created killed inactivated viruses

A

Uses chemical (formalin or phenol treatment) or heat inactivation to kill pathogen, which is then used in the vaccine, sometimes with an additional adjuvant

256
Q

What was initially used to prevent Smallpox?

A

Variolation

257
Q

Why was Smallpox successfully eradicated?

A
  • A stable, cheap, very efficacious (90‐97%) vaccine available
  • The reservoir was limited:
    • Only infects humans (no animal reservoir)
    • Infected died or resolved infection (no chronic infection)
    • Infection was easily recognised (isolate the infected)
  • Only 2 viral variants (variola major and variola minor)
  • Intensive, co‐ordinated, global surveillance‐ ring vaccination
258
Q

What is the name of the activated vaccine used to treat polio? What were the negatives?

A

Trivalent Oral polio vaccine (tOPV)

  • Developed by Albert Sabin (1963)
  • Live attenuated vaccine (3 strains)
  • Very effective at inducing immunity
  • Easy to administer (oral)
  • But it can:
    • Revert to virulent virus
    • Cause vaccine‐induced paralysis
259
Q

What is the name of the inactivated Polio vaccine? What is its negatives?

A

Trivalent Inactivated Polio Vaccine (tIPV)

  • Developed by Jonas Salk (1955)
  • Inactivated vaccine (3 strains)
  • Virus is formalin inactivated
  • Not as effective at inducing immunity
  • Have to inject the vaccine
260
Q

Why did the Cutter Incident occur?

A
  • Inexperience at lab
  • Lack of federal regulation
261
Q

What is the name of the inactivated Pertussis vaccine? What are its negatives?

A

First vaccine was known as the “whole cell” vaccine (DTwP)

  • Formulated with diphtheria and tetanus toxins
  • Inactivated vaccine
  • Treat bacteria formalin to inactivate the bacteria and toxin
  • Adjuvanted with alum
  • Issues with reactogenicity‐ high rate of fevers and seizures
262
Q

What is the name of the acellular subunit Pertussis vaccine? What is its negatives?

A

New pertussis vaccine is known as the “acellular” vaccine (DTaP)

  • Subunit vaccine
    • 3‐5 purified pertussis antigens, including the inactivated toxin
    • Alum adjuvant
  • Much less reactogenic but immunity is less effective and wanes quickly, so an adolescent boost (TdaP) was added:
263
Q

How do you make a recombinant vaccine?

A
  • Identify antigen of interest
  • Clone the gene coding that antigen into an expression system that grows, produces protein at a high rate (i.e. yeast)
  • Purify the protein antigen
264
Q

What are the differences between polysaccharide-only and conjugate vaccines?

A
  • Bacterial capsules made of polysaccharide are targets for antibody
  • But polysaccharide isn’t immunogenic for T cells:
    • Polysaccharide‐only vaccines lack CD4 T cell help for B cell responses and immunity is weak and short‐lived
  • Conjugate polysaccharide to immunogenic protein (i.e toxoid):
    • In conjugate vaccines, a CD4 T cell response to the protein provides “help” for the B cell response to the polysaccharide
265
Q

What are the pros and cons of Live Attenuated vaccines?

A

Pros:

  • Induces strong life-long immunity for antibody and T-cells

Cons:

  • Can cause more severe side-effects
  • Can cause disease in immunocompromised people
  • Chance of reversion of virulence
266
Q

What are the Pros and Cons of Killed Inactivated vaccines?

A

Pros:

  • Can induce strong, long-lasting immunity

Cons:

  • Reliant on effective inactivation
  • Can be more reactogenic
267
Q

What are the Pros and Cons of Subunit vaccines?

A

Pros:

  • Very safe
  • Can induce antibody immunity

Cons:

  • Not good for T-cell imunity
  • Immunity may wane or be less effective at preventing infection
  • Requires multiple shots
268
Q

How are viral vector vaccines made?

A

Take a harmful pathogen:

  • Identify gene for a target antigen

Take a minimally pathogenic virus:

  • Remove genetic material associated with virulence
  • Insert target antigen

Infects cells like vector virus:

  • Not virulent
  • Expresses target antigen
269
Q

What is the antigen for viral vector vaccines?

A

inserted gene that encodes the required protein

270
Q

What is the adjuvant for viral vector vaccines?

A

viral particle increases uptake, several viral danger signals (dsRNA‐ TLR3; ssDNA‐ TLR7; etc)

271
Q

What are the advantages of viral vector vaccines?

A
  • Very safe
  • Quick and cheap to make (pandemic situations)
  • Mimics a “live” infection more closely because it combines mechanisms of adjuvancy
272
Q

What are the disadvantages of viral vector vaccines?

A

Pre‐existing immunity to the virus used as the vector may limit immune responses

273
Q

Which viral vector was used to make the ebola vaccine?

A

Vesicular stomatis virus (VSV)

274
Q

What does attentuation remove and what does it retain?

A

Remove: Virulence factors

Retain: Infectivity

275
Q

Name one eradicated pathogen

A

Smallpox

276
Q

Name one near-eradicated pathogen

A

Polio

BMS2052 (6 decks)

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