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BMS2052 MICRO > WEEK 8: ANTIMICROBIAL AGENTS AND RESISTANCE > Flashcards

WEEK 8: ANTIMICROBIAL AGENTS AND RESISTANCE Flashcards

1
Q

What are examples of early antimicrobials found from the environment?

A
  • Quinine (in tonic water) for malaria

- Mercury for syphilis

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2
Q

What did Alexander Flemming discover that inhibited the growth of S. aureus?

A

-Penicillin

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3
Q

What is the 1942 definition of an antibiotic? (By Waksman)

A
  • Any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution
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4
Q

What is a main general property of antimicrobial agents?

A
  • Selective toxicity
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5
Q

What does the property of selective toxicity involve and what is an example of it?

A
  • Antimicrobial agent that needs to target a biochemical process that occurs IN THE PATHOGEN but preferably not in the host
    e. g. Penicillin targets the biosynthesis of peptidoglycan in bacterial cell walls (there is no such pathway in mammalian cells so they are safe)
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6
Q

In general, are narrow spectrum or broad sprectrum antimicrobial agents better?

A
  • Narrow spectrum bc. it doesn’t destroy the microbiome

- Effective only against a limited number of bacteria (less resistance)

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7
Q

What are narrow spectrum antimicrobial agents effective against?

A
  • Only a limited number of bacteria
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8
Q

What are broad spectrum antimicrobial agents effective against?

A
  • Many different types of bacteria

- they are like a bomb and take out everything, even the good bacteria

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9
Q

What are the three different classes that antimicrobial agents can com from?

A
  • Natural products
  • Semisynthetic products
  • Synthetic products
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10
Q

What are examples of antimicrobial agents sourced 100% from natural products?

A
  • Penicillin, aminoglycosides and polyenes
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11
Q

How are microbial agents sourced from natural products?

A
  • by fermentation of fungi or bacteria that produce the antimicrobial agents (like penicillin)
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12
Q

What are semisynthetic products in terms of the source of antimicrobial agents and what are some examples?

A
  • Chemically modified derivatives of natural products

- E.g. beta-lactams, cephalosporins

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13
Q

Are completely synthetic products common or rare for the source of antimicrobial agents?

A
  • Rare
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14
Q

What are completely synthetic products in terms of antimicrobial agents and what are 2 examples of them?

A
  • Chemically synthesized

e. g. Oxazolidinones and quinolones

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15
Q

What are the names of two different effects that antimicrobial agents can have on bacteria?

A
  • Bacteriostatic agent

- Bacteriocidal agents

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16
Q

What do bacteriostatic agents do?

A
  • STOP bacterial growth but don’t kill the bacteria (Doesn’t kill them)
  • Allow host defence mechanisms to overcome infection
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17
Q

What do bacteriocidal agents do?

A
  • Kill the targeted bacterial cells
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18
Q

Do bacteriocidal agents always target the cell wall when killing the bacteria?

A

-YES

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19
Q

Can antimicrobials be bacteriocidal for one organism but bacteriostatic for the next?

A
  • YES

- bc. depends on what they target

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20
Q

What are 3 ideal conditions for antimicrobial targets?

A
  • Macromolecules (enzymes) that are UNIQUE to microbial cell or HIGHLY divergent from their human homologues
  • Metabolic processes that can be by-passed in humans but NOT in the pathogen (e.g. folate incorperation from dietary sources)
  • Normal activity of the target must be LIMITING for microbial replication or virulence
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21
Q

What are the three very basic steps to peptidoglycan synthesis?

A
  • Basic monomer
  • Extend monomer into chains
  • Crosslink the chains into a mesh like structure
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22
Q

What does PBP stand for?

A
  • Penicillin Binding Protein
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23
Q

What three processes in cell wall synthesis and maintenance of Peptidogylcan do PDPs have a role in ?

A
  • Transglycosylation
  • Transpeptidation
  • Peptide cleavage
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24
Q

What does transglycosylation involve in cell wall synthesis of bacteria

A
  • Wall synthesis for growth and septation (division into parts by septum) of bacteria
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25
Q

What does transpeptidation involve in cell wall synthesis in bacteria?

A
  • Crosslinking and remodelling (sticking the peptide bonds together)
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26
Q

What does peptide cleavage involve (i.e. what is being cleaved) in the maintenance and cell wall synthesis of bacteria?

A
  • D-ala carboxypeptidases and endopeptidases cleaved

- Control of crosslinking and insertion of new strands

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27
Q

What is a CRUCIAL part of the cell wall formation and maintenance processes (glycoslyation, transpeptidation and peptide cleavage)?

A
  • Recognition of D-Ala-D-ALa (need to target this part!)
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28
Q

Interfering with the recognition of what disrupts the cell wall synthesis in bacteria?

A
  • Recognition of the D-Ala-D-Ala link
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29
Q

In cell wall synthesis of bacteria, what are MAJOR antibacterial targets?

A
  • PDBs
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30
Q

In Beta lactam antibiotics, what does the beta lactam ring mimic and how does this disrupt the crosslinking process?

A
  • It mimics the structure of D-Ala-D-Ala link and binds to the SAME place IN the PDBs (active site) as the natural substrate
  • THUS DISRUPTING THE CROSSLINKING PROCESS
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31
Q

What effect do Beta lactams have on PDBs?

A

-they inactivate them by mimicing the natural substrate and binding to the active site in the PDBs, and deactivating it by blocking the ACCESS for the natural substrate

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32
Q

Where do Penicilling Binding Proteins (PDBs) bind to normally?

A
  • The
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33
Q

What is the D-Ala-D-Ala sequence part of?

A
  • The MurNac-glcNac pentapeptide
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34
Q

Do Beta lactams have different affinities for different PBPs and different effects on target cells?

A
  • YES
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35
Q

Are beta lactams bacteriostatic or bacteriocidal for actively growing cells?

A
  • Bacteriocidal
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36
Q

How does resistance to beta lactams occur/what does it occur through?

A
  • Production of Beta lactamases OR PBP and porin mutations
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37
Q

Are beta lactam antibiotics narrow or broad spectrum, what is their mode of delivery normally, and are they bacteriocidal or bacteriostatic?

A
  • Broad spectrum (targeting D-Ala-D-Ala in all bacteria)
  • Oral delivery
  • Bactericidal
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38
Q

Have beta lactams evolved mutations over time?

A
  • YES

- to the point where there are different members of the family

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39
Q

What is the rough mode of action of beta lactams?

A
  • NEW peptidoglycan material is inserted into old wall at specific points
  • BLOCKED peptidoglycan crosslinking induces FUTILE cycle of peptidoglycan turnover and DEREGULATES autolytic activities
  • UNDER-crosslinked Peptidoglycan (PG) provides LESS support against turgour or osmotic pressure
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40
Q

What two classes of antibiotics act on the cell wall process and maintenance of bacteria?

A

-Beta lactams and Glycopeptide antibiotics

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41
Q

What is an example of a glycopeptide antibiotic?

A
  • Vancomycin (and teicoplanin)
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42
Q

What is the mode of action of glycopeptide antibiotics?

A
  • They bind to the terminal D-Ala-D-Ala DIPEPTIDE inhibiting transglycosylation and transpeptidation of peptidoglycan (PG)
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43
Q

Are glycopeptide antibiotics bacteriostatic or bacteriocidal, what is their spectrum, and what are they usually used to treat?

A
  • Bactericidal
  • Gram positive spectrum
  • Usually treat C. difficile (chlostridioides difficile) infections like antibiotic associated colitis
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44
Q

What is the last resort antibiotic for the treatment of multiple antibiotic resistant S.aureus?

A
  • glycopeptide antibiotics like Vancomycin
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45
Q

What makes antimicrobial targeting bacterial ribosomes have SELECTIVE toxicity?

A
  • Differences in the bacterial/eukaryotic ribosomes
46
Q

Which types of antibiotics bind to the 30S subunit of the ribosome and what are 2 examples?

A
  • Amino acyl-tRNA blockers
  • Decoding disruptors
    e. g. Aminoglycosides, and Tetracyclines (doxycyline)
47
Q

Which types of antibiotics bind to the 50S subunit of the ribosome and what are some examples?

A
  • Peptidyl transferase inhibitors
  • Exit tunnel blockers
    e.g. macrolides (erythromycin)
    Lincodamines (clindamycin)
    Oxazolidinones (linezolid)
    Chloramphenicol
48
Q

What is tetracycline antibiotics general structure and mode of action?

A
  • 4 ringed family of compounds

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

49
Q

Are tetracycline antibiotics bacteriocidal or bacteriostatic, what is their spectrum and how are they administered (biovavilability), what are they active against and how to they obtain resistance?

A
  • Bacteriostatic
  • BROAD spectrum
  • ORALLY bioavailable
  • Active aginast intracellular pathogens
  • Obtain resistance through EFFLUX or RIBOSOMAL protection proteins
50
Q

What is the basic structure of aminoglycosides (the ones that target the 30S subunit) ?

A
  • Cyclohexane ring and amino sugars
51
Q

Under aerobic conditions, what are aminoglycoside antibiotics effective agsint?

A
  • gram negative bacteria
52
Q

What is the mechanism of action of aminoglycosides?

A
  • Interferes with proof-reading process for incoming aa-tRNA –> this results in premature termination OR proteins with amino acid substitutions
53
Q

Are there any semisythetic options for aminogylcosides (targeting 30S subuint)?

A
  • LIMITED semisynthetic options
54
Q

Are aminoglycosides bactericidal or bacteriostatic, are they orally bioavailable, and how do they acquire resistance?

A
  • Bacteriocidal
  • NOT orally bioavailable (only available through IV in hospitals)
  • Acquire resistance through target mutations and modifying enzymes
55
Q

What is the general structure of macrolides and what is their mechanism of action (i.e. what do they target)?

A
  • 12-24 C lactone ring to one OR more sugars
  • Binds REVERSIBLY to 23S rRNA in 50S subunit (targets the 50S subunit)
  • This disrupts the movement of tRNA from A site –> P site –> INHIBITS peptide chain elongation
56
Q

What type of bacteria do macrolides target, what is their spectrum, what is their bioavailability, are they bacteriostatic or bacteriocidal?

A
  • Target gram +ve mostly
  • Broad spectrum
  • Orally biovailable
  • Bacteriostatic
57
Q

What types of pathogens are macrolides active against ?

A
  • Legionella, Mycoplasma, Chlamydia
  • These are all intracellular pathogens
  • bc. Macrolides enter and accumulate in eukaryotic cells like macrophages
58
Q

What are 3 resistance mechanisms of Macrolides?

A
  • Target modification (RNA methlyation)
  • Efflux (pumping it out)
  • Enzymatic modification
59
Q

Are Oxazolidinones natural, semi-synthetic, or synthetic antibiotics?

A
  • Completely synthetic (new class)
60
Q

What is the mode of action of Oxazolidinones?

A
  • Bind to the rRNA on the A site of the Peptidyltransferase centre (PTC) of RIBSOSOME
61
Q

What is the bioavilability of Oxazolidinones, are they bacetriocidal or bacteriostatic, what type of spectrum do they have (what type of bacteria do they act on), what are they used for and what is resistance mediated through?

A
  • Bacteriostatic
  • Gram positive and M.tb spectrum
  • Used for multiply drug resistant organisms
  • Resistance is mediated through rRNA mutations
62
Q

Did resistance to the fully synthetic antibiotic Oxazolidinones develop slowly or quickly?

A
  • QUICKLY

- Within roughly 2 years

63
Q

What are the two classes of antibiotics that target the 50S subunit?

A
  • Oxazolidinones and Macrolides
64
Q

What is the class of antibiotics that targets DNA replication thus acting as a DNA replication inhibitor?

A
  • Fluroquinolones
65
Q

What are the two classes of antibiotics that target Transcription thus acting as transcription inhibitors?

A
  • Rifamycins and Fidaxomicin
66
Q

What is the basic structure of Fluoroquinolones and what is their mode of action?

A
  • Synthetic antimicrobials with QUINOLONE ring (e.g. Ciprofloxacin and Moxifloxacin + Nalidixic Acid)
  • Mode of action: Bind to DNA gyrase and topoisomerass BLOCKING the formation of the complex with NICKED DNA
  • Thus BLOCK DNA REPLICATION AND DNA REPAIR
67
Q

What is the bioavailability of Fluoroquinolones, spectrum, bactericidal or bacteriostatic, what are they useful for, and how do they acquire resistance?

A
  • Orally bioavailable
  • Broad spectrum
  • Bactericidal
  • Useful for UT and GI infections, anthrax, legionellosis, and pneumonia
  • Acquire resistance through gyrA and gyrB mutations and expression of gyrase-binding proteins
68
Q

How do Fluoroquinolones acquire resistance?

A
  • Acquire resistance through gyrA and gyrB mutations and expression of gyrase-binding proteins
69
Q

What is the action of Rifamycins and Fidaxomicin?

A
  • They bind to DNA -dependent RNA polymerase and BLOCK the synthesis of mRNA thus blocking traslation
70
Q

Are rifamycins (translation inhibitor) natural, semi-synthetic or completely synthetic compounds?

A
  • Semi synthetic
71
Q

Are rifamycins baceriostatic or bactericidal, what is hteir spectrum, what is their biavailability?

A
  • Bactericidal
  • RELATIVELY broad spectrum
  • WELL absorbed ORALLY and distributed throughout the body
72
Q

Can Riafmycins cross the blood-brain barrier?

A
  • YES
73
Q

What are Rifamycins used for? (reserved for)

A
  • Mycobacerial infections
  • Prophylaxis
  • Haemophillus close contacts (only get in hospitals)
74
Q

Is Fidaxomycin a natural, semi or fully synthetic product, what is its bioavailability, and is it an old or new antibiotic + what infections is it used for?

A
  • Natural product
  • Not orally bioavailable
  • New antibiotic used for C.difficile infections
75
Q

What are metabolic antagonists?

A

Antimicrobials that BLOCK or INHIBIT metabolic pathways

76
Q

What are two examples of metabolic antagonists?

A
  • Sulphonamides and trimethoprim
77
Q

What is the spectrum of metabolic antagonists (Sulphanomides and Trimethoprim) and are they baceriostatic or cidal?

A
  • BROAD spectrum

- Bacteriostatic

78
Q

Are metabolic antagonists (Sulphonamides and Trimethoprim) selective and if so why?

A
  • SELECTIVE

- Bc. humans obtain folic acid from the diet and human dihydrofolate reductase is RELATIVELY RESISTANT to trimethoprim

79
Q

What are Sulphonamides analogues of?

A
  • p-aminobenzoic acid
80
Q

What is trimethoprim a competitive inhibitor of?

A
  • dihydrofolate reductase
81
Q

How is resistance mediated in Metabolic antagoinsts?

A

-By target mutations

82
Q

In developing antifungal agents, what are 4 targets that can prevent the growth of fungus?

A
  • Glucan synthesis inhibitors
  • Thymidine analogues (pyrimidine salvage pathways)
  • Ergosterol binders
  • Ergosterol synthesis inhibitors
83
Q

Why are fungi the hardest type of organism to target with animicrobials ?

A
  • Bc. they are EUKARYOTES
84
Q

Is antimicrobial resistance a serious threat to global health?

A
  • YES
85
Q

Is antimicrobial resistance a significant burden on health care systems and society?

A
  • YES
86
Q

What is a last resort of antimicrobial resistance?

A
  • Phage therapy
87
Q

Will there ever be an antibiotic that is resistant proof?

A
  • NO
88
Q

What are the three different types of resistance?

A
  • Intrinsic resistance
  • Acquired resistance
  • Tolerance
89
Q

What does intrinsic resistance involve?

A
  • Lack of a susceptible target
  • Target protection mechanism
  • Impermeable to agent (influx/efflux)
  • Pre-existing modifying enzyme
  • (gram -ve)
90
Q

what does acquired resistance involve?

A
  • Spontaneous mutations

- Acquisition of resistance genes

91
Q

What does tolerance involve?

A
  • Bacteria are STILL inhibited BUT DO NOT LOSE VIABILITY and they RECOVER after antibiotic disappears
    i. e. doesn’t grow but doesn’t die
92
Q

What are 3 different ways bacteria can become resistant to antimicrobials?

A
  • Acquired resistance by mutation
  • Plasmid mediated resistance on a transposon
  • Plasmid mediated resistance –> spread of resistance plasmid
93
Q

What are the 3 mechanisms of drug resistance?

A
  • Modification or inactivation of antibiotic
  • Modified antibiotic transport
  • Lowered affinity for antibiotic
94
Q

What does modification or inactivation of the antibiotic (mechanism of drug resistance) involve?

A
  • Produces enzymes that alter actual antibiotic –> includes beta-lactamases, aminoglycoside-modifying enzymes and reifamycin ADP-ribosylase
95
Q

What does modified antibiotic transport involve? (mechanism for drug resistance)

A
  • Decreased cell wall permeability

- Active efflux (pumping the drug out!)

96
Q

What does a lowered affinity for the antibiotic involve? (mechanism for drug resistance)

A
  • Binding site alteration
  • Enzymatic modification
  • PROTECTION FROM ANTIBIOTIC BINDING
97
Q

What are two ways that the modification or inactivation of an antibiotic can be achieved?

A
  1. Inactivate drug by chemically cleaving it

2. Modification of the antibiotic molecule

98
Q

What are two ways that antibiotic transport can be modified?

A
  1. Decreased cell wall permeability

2. Increased efflux from the cell

99
Q

What are two ways that the target site can be modified to combat antibiotics?

A
  • Alteration of the target site to reduce the susceptibility of the antibiotic
  • Acquisition of the genes encoding enzymes that alter target
100
Q

What do Erm enzymes stand for and what do they do?

A
  • Methylate A2058 residue of 23S RNA –> this reduces the ability of the macrolides to bind to the ribosomal target
101
Q

What is an example of the acquisition of genes encoding enzymes that alter the target in combatting antibiotics?

A

Vancomycin resistance
- Vancomycin binds to TERMINAL D-Ala-D-Ala and BLOCKS PG synthesis
- Vancomycin resistance involves acquisition of genes encoding enzymes that alter D-Ala-D-Ala –> D-Ala-D-Lac
This reduces the binding of Vancomycin drug (Stops PBP from binding to cell wall)

102
Q

What are Carbapenems?

A
  • Beta-lactam antibiotics  e.g. Thinamycin (from Stephtomyces cattleya) which was Beta lactamase inhibitor
  • Thinamycin was the blueprint for all future Carbapenems
  • More BROAD SPECTRUM than penicillins or cephalosporins
103
Q

Are Carbapenems more broad spectrum than penicillins and cephalosporins?

A
  • YES
104
Q

What is involved in Carbapenan resistance?

A

-North Carolina Strain produced enzyme called KPC –> Klebsiella pneumoniae carbapenemase –>encoded on the BLAkpc gene which was on a plasmid (in Tn3-like transposon)

105
Q

What is NDM-1?

A
  • New Dehli metallo-beta-lactamase
106
Q

Where is the BLAndm gene found?

A
  • On transposon 125
107
Q

Where is NDM-1 found today?

A
  • On MULTIPLE broad host range plasmids that often co-harbour other resistance genes (resistance cassette)
  • Gene found in ALL Enterobacteriaceae –> Acinetobacter, K.pneumoniae, E.coli, Pseudomonas spp, Vibrio cholerae
  • Global distribution
  • 11 known variants
108
Q

What does MCR-1 act to do?

A
  • It is phosphoethanolamine (pEtN) transferase that acts to MODIFY the phospholipid head group –> reduces the ability of colistin to bind to its target
109
Q

HOW DO WE TREAT PATIENTS WITH RESISTANT GRAM -VE INFECTIONS?

A
  • Beta lactams were GOLDEN BULLET for LONG TIME with gram -ve pathogens
  • Treatments now are: Tigecycline (tetracycline derivative) or Colistin (aka polymyxin E)–> BUT this is toxic as there is poor pharmacokinetics –> Polymixins = kidney and neurotoxicity and Tetracyclines= GI side effect
110
Q

What does MCR-1 stand for?

A
  • Mobilized colisin resistance-1
111
Q

What are polymixins?

A
  • NON-ribosomal, cyclic peptides
112
Q

What is the action of colisin (polymixin)?

A
  • Bind LPS and phospholipids of outer cell membrane of gram -ve bacteria
  • Disrupt BOTH inner and outer membranes –>Bactericidal

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