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33. Antibiotics Flashcards

1
Q

Essay plan structure

A
  • INTRODUCTION
  • BACTERIAL SURFACE STRUCTURES
    • ​Gram stain technique
    • Peptidoglycan
    • ​Gram negative cell structures
      • ​Outer membrane
      • Lipopolysaccharide (LPS)
      • Porins
      • Type 3 Secretion Systems
    • ​Gram positive cell wall structures
      • ​Teichoic acid
    • Features of both
      • Flagella
      • Pilli
  • ​​​CLASSIFICATION OF ANTIBIOTICS
    • ​Bactericidal
      • ​Inhibition of cross linking
    • ​Inhibits protein synthesis (EGMAT
      • ​50 s
      • 30s
    • ​​Myobacterium (iconiazid)
  • ​CONSIDERATION OF ADMINISTRATION
  • GENETIC BASIS OF BACTERIAL RESISTANCE
    • ​Chromosomal mediated resistance
    • Transposon mediated resistance
    • Plasmid mediated resistance
  • ​BIOCHEMICAL BASIS OF RESISTANCE
    • ​Drug inactivation
    • Modification of dug target
    • Reduced intracellular concentration
    • Increased efflux
    • Biofilm formation
  • ​SELECTION PRESSURES
    • ​Hospitals
  • ​FUTURE DIRECTION
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2
Q

Cell summary

A
  1. (DD–)Transpeptidase (structural)
    • Penicillin (beta–lactam)
    • Cephalosporins
  2. Blocks bacterial RNA polymerase (transcription)
    • Rifampicin (rifamycins)
  3. ​​Inhibit synthesis of 50s ribosome subunit (translation)
    • Erythromysin (macrolide) prevents A–>P
  4. Inhibits 30s ribosome subunit (translation)
    • Gentamycin (aminoglycoside) - acceptance of incorrect AA-tRNA complexes
    • Tetracyclin - blocks A site
  5. Inhibits folic acid synthesis by inhibiting dihydropterate synthetase (replication)
    • Sulfonamids
  6. ​ Inhibits folate synthesis by inhibiting dihydrofolate reductase (replication)
    • Trimethoprim (diaminopyridines)
  7. Inhibits topoisomerase IV and DNA gyrase
    • ​Ciprofoxacin (fluoroquinolines)
  • For gram positive bacteria, topoisomerase IV is the target
  • For gram negative bacteria, DNA gyrase is the target
  • RNA polymerase = converting DNA into RNA (transcription)
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3
Q

Qualities of a successful antibiotic

A
  • Selectively toxic to the bacteria
  • Target and inhibit an essential bacterial function
  • Have a wide therapeutic index
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4
Q

Perceptive opening about antibiotics

A
  • Before the start of the 20th century, infectious diseases were the leading cause of death worldwide
  • The purification of the first antibiotic by Chain & Florey 1942 was of great significance, allowing the treatment of and recovery from infected cuts and wounds that were previously fatal
  • It also dramatically reduced the risk of surgery and invasive procedures that increase the risk of infection and fatality
  • The initial success prompted the Golden Era for the Discovery of Antibiotics (1950-1970) and since then the development of new classes has been slow o Their relative effectiveness, coupled with few side effects resulted in their widespread, global use in the treatment of bacterial infection.
  • Which, alongside their widespread use in the farming industry has led to many bacteria becoming resistance to them
  • Antibiotic resistance is the ability of a bacteria to become resistant to AB they were previously sensitive to
  • Multiple drug resistant bacteria result in the death of more than 25,000 people worldwide (CDC)
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5
Q

Gram staining method

A
  • Gram-positive bacteria have a thick mesh-like wall made up of peptidoglycan
  • (50-90% of cell envelope) whereas Gram-negative bacteria have a thinner layer (10% of cell envelope)
  • Crystal violet (primary dye)
    • CV+ ions and Cl- ions penetrate the cell wall of both Gram-positive and Gram-negative bacteria
    • CV+ ion interacts with negatively charged components staining the cell purple
  • Iodine (trapping agent)
    • Iodine (I- or I3-) interacts with CV+ and forms large complexes of crystal violet and iodine (CV-I within the inner and outer layers of the cell
  • Alcohol (decolouriser)
    • Gram negative cell loses its outer lipopolysaccharide membrane and the inner peptidoglycan layer is left exposed
    • CV-I complexes washed from gram-negative cell along with outer membrane
    • In contrast, gram-positive cell becomes dehydrated from an ethanol treatment
  • Carbachol fuchsin (counter stain)
    • Wash
    • Washing away carbachol from gram positive bacteria
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6
Q

Why can mycobacteria e.g. M tuberculosis not be visualised with gram stain?

A

• High cell wall lipid so no dye penetration • Use of acid fast stain instead

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7
Q

Why can treponema pallidum not be visualized with gram stain?

A

• Too thin to see • Use of dark-field microscopy or fluorescence antibody instead

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8
Q

Why can mycoplasma pneumonia not be visualised with the gram stain?

A

• No cell wall, small • No other alternative methods

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9
Q

Why can legionella pneumophila not be visualised with gram stain?

A

• Poor uptake of red counterstain • Increased duration of counterstain to compensate

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10
Q

Why can chlamydia not be visualised with gram stain?

A

• Intracellular, too small • Inclusion of bodies in infected cell cytoplasm

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11
Q

Draw out the gram positive structure and describe it

A
  • Envelope consists of a single plasma membrane internal to a thick layer of PG (15-180 nm thick) with a wall of teichoic acid on top
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12
Q

Draw out the gram negative structure

A
  • Inner membrane
  • Thin peptidoglycan layer in the inner periplasmic space
    • 2nm thick as opposed to 15-80 nm thick for gram-positive
  • Outer membrane contains lipopolysaccharide (LPS)
    • LPS = endotoxin
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13
Q

Define a peptidoglycan and its function

A
  • Structure
    • Glycan layer of alternating N-acetylglucosamine sugars and N-acetylmuramic acid residues connected by 1,4-glycosidic bonds
    • Each MurNac residue is bonded to a peptide chain of 3-5 alternating L and D amino acids
      • Precise composition differs between bacteria
    • Peptide chains are connected to adjacent chains by peptide cross links
      • DIffers in sructure between gram-positive and gram-negative bacteria
  • Function
    • Rigid support of the cell
    • Maintenance of cell shape
    • Resistance to osmotic pressure, preventign changes in bacterial cell volume
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14
Q

How do beta-lactam antibiotics target peptidoglycans? Outline the mechanism and the effect. Which gram group is more susceptible?

A
  • PG is expressed only in bacteria, making it a good target for antibiotic action as host cells are unaffected
  • Beta lactam antibiotics such as penicllin, carbapanems and cephalosporins inhibit PG syntehsis
  • ​​Mechanism
    • ​They first bidn to one of many beta-lactam binding proteins
    • They inhibit the transpeptidase enzyme that forms the peptide crosslinks between the peptide chains
  • ​Effect
    • ​This prevents PG synthesis is new bacterial cells, having a bacteriostatic effect
      • ​Bacteriostatic effect = reducing bacterial division
    • ​Their bactericidal effect is mediated by the activation of autolytic enzymes in the cell wall, leading to bacterial lysis
  • ​Effectiveness
    • ​Less effective for gram negative bacteria as they have a layer of LPS preventing penetration and making PG less accessible
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15
Q

Mechanism of lysozyme-mediated destruction of bacteria

A
  • Lysozyme = enzyme in human tears
  • Cleave sglycosoidic bonds in the glycan backbne of PG
    • ​Bacterial cell loses osmotic resistance and thus swells and lyses in low osmolarity solution
    • Mechanism of antimicrobial defence associated with the barriers of innate immunity
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16
Q

Describe the gram negative outer membrane

A
  • Description
    • Lipid bilayer with an asymmetric chemical distriution
    • Inner leaflet made of phospholipid whereas outer leaflet is mainly made of lipopolysaccharide (LPS)
  • Functions
    • Permeability barrier against compounds
      • Bile
      • Antimicrobials such as bile and antimicrobials
    • Produces outer membrane vesicles (OMVs)
      • Host antibodies so they bind to the vesicles instead of the bacterium thus acting as an immune decoy mechanism
    • ​Target for insertion of membrane attack complex
      • ​Mediates bacterial lysis in terminal effector stage of complement pathway
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17
Q

Which gram-stained bacteria are lipopolysaccharides found? Describe their structure and function of each subcomponent

A
  • Gram negative
  • Lipopolysaccharides = macromolecules consisting of lipids and polysaccharides that are expressed in the outer membrane of the gram-negative envelpoe
  • Structure
    • ​Lipid A
      • Fatty acids and disaccharide-diphosphate group embeded in the lipid bilayer of the outer membrane
      • Endotoxin component of LPS
    • Core polysaccharide
      • Inner core of five sugars linked to lipid A via ketodeoxyoctulonate (KDO) and outer core sugars
    • O-antigen
      • ​Polysaccharide chain attached to core polysaccharide
        • ​Core plyscharide is made up of a repeating oligosaccharide unit consistign of 3-5 sugar residues
      • Variable in length and composition
      • Used to identify bacterial species such as Neisseria genus which have a non-enteric O-antigen (non-O-antigen)
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18
Q

Which gram-type will porins be found on? Outlien their structure and function. Which antibiotics can pass through it?

A
  • Porins = channel proteins in the outer memrbane of Gram-negative bacteria and mycobacterium
  • Facilitates entry of hydrophilic substances into the periplasmmic space
    • Hydrophilic drugs enter through it
      • ​Beta lactams
      • Tetracycline
    • Hydrophobic enter by diffusion (MA)
      • ​Aminoglycosides
      • Macrolides
  • ​​Structure
    • ​Made from polyppetides that assemble into beta-barrel domains and form the pore channel
    • Size of around 600 Daltons
    • Antibiotics must be smalelr than this to pass through
      • ​Mutations madiate resistance
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19
Q

Which Gram stain can Type 3 secretion systems be found? Define their structure and function

A
  • In cell wall of gram-negative bacteria
  • Used to inject bacterial toxins into the host cell cytoplasm
  • Structure
    • Over 20 different proteins assemble to form the secretion system
    • Span the inner and outer membrane
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20
Q

Which gram type has flagella? Defien theri structure and function

A
  • Both gram negative and gram positive
  • Description
    • Flagella = long filament extending from the bacterial surface that drives cell motility/locomotion
    • Conformational changes in the protein machinery drive rotation of the filament, propelling bacteria through aqueous solution
  • Function
    • Chemotaxis
      • Directional movement in response to a chemical stimulus
    • Facilitating movement towards nutrients
  • Structure
    • Basal body
      • Protein complex embedded in cell envelope that drive smovement via energy from teh discharge of a proton gradient
      • Utilises ATP synthase
    • Hook
      • Made of flagellin E
      • Length of 60 nm
    • Filament
      • Composed of 20,000 to 30,000 flagellin subunits in a helical arrangement
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21
Q

Which gram type has pilli? Describe its structure and function

A
  • Both gram positive and gram negative
  • Pili are filaments on the bacterial surface made of pilin subunits in a helical arrangment
  • Functions
    • Attachment
      • Faciliates adherence to host surface at start of infection
      • Retraction of pilus towards receptors
        • Importance highlighted in aivurlent mutations of Neisseria gonorrhea that lack pilli o receptors on surface of host cells
      • Facilitates adherence to host surface at start of infection
    • Conjugation
      • Sex pilus facilitates the transfer of plasmid DNA between donor and recipient bacterium
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22
Q

Define bactericidal

A
  • Usually affect cell wall synthesis
  • Preventign its formation and hence bacterial replication
    • Cell lysis
23
Q

Define bacteriostatic

A
  • Drug that inhibit:
    • DNA replication
    • Protein synthesis
    • Growth
  • Does not kill them directly
  • Host immune mechanisms
    • ​Phagocytosis
  • ​Only effective in replicating bacteria
24
Q

Examples of bacteriostatic antibiotics

A
  • Chloramphenicol
  • Clindamycin
  • Erthryomycin
    • 50S
      • EGMA = 50S & 30S
  • Sulfamethaxazoe
    • Dihydroopterate synthase
  • Tetracycline
  • Trimethoprim
25
Q

Examples of bactericidal antibiotics

A
  • Structural
    • Beta-lactams
      • Cephalosporins
      • Carbapenam
      • Penicillin
    • Vancomycin
  • Protein synthesis
    • Gentamycin (aminoglycosides)
      • 30S
        • 50S is bcteriostatic
  • DNA
    • Fluoroquinolones
      • Topoisomerase IV & DNA gyrase

GF = exception

26
Q

Are beta lactams bacteriocidal or bacteriostatic? Discuss the structure and mechanism of action of beta-lactams

A
  • Bacteriocidal
  • Examples
    • Penicllin
    • Methicillin
    • Cephalosporin
    • Amoxicillin
      • Broad spectrum
  • Effective when bacteria are replicating and new wall is being synthesised
  • Gram positive bacteria due to exposed peptidoglycans
    • No LPS layer
  • Mechanism
    • Inhibition of PG synthesis activates peptidoglycan hydrolyses that breaks down the peptidoglycan layer and leads to osmotic lysis
  • Half life of 1 to 2 hours
27
Q

Is vancomycin bacteriostatic or bacteriocidal? Describe its structure and function as well as its toxic effects

A
  • Structure
    • Glycopeptide
  • Mechanism of action
    • Binds directly to the N-acetylglucosamine sugar and N-acetylglucamic acid portion of the PG
      • D-alanyl-D-alanine
    • Toxic effects
      • Nephrotoxicity
      • Ototoxicty
28
Q

Describe antibiotics that affect the 50s ribosome. What is their mechanism of action?

A
  • Structure
    • Antibiotics with a membered beta-lactam ring in their structure
  • Examples
    • Chloramphenicol
      • Blocks action of petidyl transferase
    • Erthyromyocin (macrolides)
      • Blocks translocation of the 50s subunit
    • Clindamycin
      • Blocks tRNA attachment
    • Linezolid
      • Premature release of the mRNA
  • Most effective
    • Gram positive and gram negative
29
Q

Outline the structure and function of antibiotics that target the 30S ribosome. For each, outline if they are bactericidal or bacteriostatic.

A
  • Aminoglycosides
    • Examples
      • Gentamycin
      • Most effective
        • Gram negative - aerobic
          • Bacillus
        • Gram negative - facultative bacilli
          • Corynebacteria and lactobacillus
    • Mechanism
      • Inhibition of the initiation complex before translation
      • Misreading of mRNA
    • Bacteriocidal
      • Creates fissures in the outer membrnae
  • Tetracycline
    • Structure
      • 4 rings and 2 amine groups
    • Mechanism
      • Blocking the tRNA from entering the acceptor site in the ribosome
      • Not specific to bacterial but is taken up preferentially by them
    • Bacteriostatic
      • Inhibits protein synthesis, preventing replication
30
Q

Describe an antibiotic that target mRNA. Outline its structure, MOA and whether it is bactericidal or bacteriostatic

A
  • Rifamycin
    • Structure
      • Amino-modified glycoside sugar
    • Example
      • Rifampicins
    • Most effective
      • Used in TB therapy
    • MOA
      • Inhibits RNA polymerase
    • Bacteriostatic
      • Inhibits protein synthesis
31
Q

Describe the antibiotics that affect DNA synthesis, their structure and their MOA.

A
  • Folate synthesis
    • ​Sulfonamides
      • Examples
        • Sulfamethaxazole
      • MOA
        • Inhibit dihydropteroate synthase
        • Not used much due to resistance
        • Used in conjunction with trimethoprim
    • Trimethiprim
      • Inhibits dihydrofolate reductase
    • ​Combination therapy
      • ​Reduces the emergence of resistant strains
      • Drugs act synergistically
        • Causing greater inhibition together than each drug separately
  • ​Fluoroquinolines​
    • Structure
      • Biyclic core structure
    • Examples
      • Ciprofloxacin
    • Most effective
      • Gram positive and gram negative
        • Enters cells via porins
    • MOA
      • Inhibits topoisomerase IV in gram postive
      • Inhibtis DNA gyrase in gram negative
    • Toxicity
      • Block GABAA receptors
        • Seizures
        • Convulsions
32
Q

Which antibiotic can be used against mycobacterium? Outline the mechanism

A
  • Iconiazid
    • ​Converted into prodrug to the active metabolite
    • Blocks fatty acid synthase
      • Inhibition of cell wall mycolic acid synthesis
33
Q

What are the factors to consider when administering an antibiotic? When are broad-spectrum antibiotics used and what would you consider?

A
  • When giving ABs, several factors are considered:
    • Tolerance / hypersensitivity
    • Type of infection
      • Gram type
      • Strain
    • Bioavailability
  • Broad spectrum
    • Specific uses
      1. Empirically
        • ​​When the cause of infection is unknown and there is the potnetial for acute onset of disease, then swtiched to narrow spectrum
      2. Superinfections
        • Mutiple bacterial infections at once
      3. Drug resistance to narrow spectrum
      4. ​Prophylaxis
        • Immunosupressed or post-surgery
    • Examples: (TACQ)
      • Tetracyclines
        • 30S (​EC GT)
      • Amoxicillin
        • Beta lactam
      • Chloramphenicol
        • 50s ribosome (EC GT)
      • Quinolones
      • Problems
        • Destruction of the microbiata and commensals leads to:
          • Resistant commensals and opportunistic pathogens
          • Overgrowth of other bacteria/fungi
            • Due to reduced competition
34
Q

What are three mechanisms that a bacteria can develop resistance?

A
  • Chromosome mediated
  • Plasmid mediated
  • Transpon mediated
35
Q

Define chromosome mediated resistance and its significance

A
  • Definition
    • Refers to a mutation of genes encoded by the circlar chromosomal DNA
  • Mutations arise spontaneously in genes that code for:
    • Target protein of drug
    • Transport system of the drug into the cell
  • Significance
    • Chromosomal mediated resistance is much less of a clinical problem than plasmid mediated resitance
      • This is because the mutation rate of chromosomal genes ranges from 10-7 to 10-9
      • This is much lower than the frequency of acquisition of resistance plasmids
36
Q

Define a transposon. Describe transposon-mediated resistance and how it arises/

A
  • Definition
    • Resistance genes transferred by transpons
      • Transposon = genes transferred within/between larger pieces of DNA
  • Structure (TRD)
    1. Transposase
      • Catalyses the excision and reintegration of the transposon
    2. Repressor
      • Regulates the synthesis of the transposase
    3. Drug resistance gene
      *
37
Q

Outline plasmid mediated resistance and its significance.

A
  • Definition
    • Resistance plasmids are extrachromosomal, circular or double-stranded DNA molecules that carry the genes for a variety of bacterial resitance mechanisms
  • Significance
    • Transmitted by conjugation with a high transmission as they replicate independently of the chromosome
      • More copies in a cell
      • Increases probability of transmission
    • Occurs in many bacterial species
    • Mediate resistance to multiple drugs
  • Transmission of resistances genes between and within bacteria
    • Horizontal gene transfer
      • Intra-genomic
      • Inter-genomic
38
Q

Outline different mechanisms of intergenomic plasmid mediated resistance.

A

CTT

  1. Conjugation
    • Conjugation = transmission of genetic material from one bacterial cell to another via sex pilus that connects the cytosolic compartments
    • Main mechanism for spread of resistance
    • Sex pilus proteins mediates transfer
      • Coded for by conjugative plasmid which is then subject to transmission
    • Non-conjugative plasmids can be transferred alongside conjugative plasmids
    • Common in high density bacterial populations
      • Bacteria found in gut
  2. Transduction
    • Transduction = plasmid DNA in a phage is transferred to another bacterium of the same species
      • Phage = bacterial virus
    • Occurs between straisn fo staphylococci and streptococci
    • Stages
      • Phage DNA enters the bacterial cell
      • Phage cuts up bacterial DNA
      • Some bacterial DNA packaged into phage heads
      • Bacterium lyses & new phage particles are released
      • Injects a new bacterial cell
      • This may be incorporated into bacterial chromosome
  3. Transformation
    • Transformation = uptake of DNA from the environment and incorporation of the DNA into the genome by homologous recombination
39
Q

Outline how resistance to beta-lactam groups is achieved.

A
  • Staphylococcus aureus
    • Express insensitive beta-lactam binding proteins AKA penicillin binding proteins
      • Beta-lactma binding proteins = enzymes that catalyse peptidoglycan remodelling
        • Transpeptidsases
        • Transglycolyases
  • MRSA
    • Acquisition of non-native gene encoding a PBP2a
      • PB2A = version of penicillin binding protein
      • Significantly lower affinity for beta-lactams
      • This gene allows for cell-wall biosynthesis, target of beta-lactams to continue even int he presence of a typically inhibitory concentration of antibiotic
40
Q

How can bacteria develop resistance to vancomycin?

A
  • D-Ala-D-Ala sequence that vancomycin targets is replaced with D-Ala-D-lactate sequence
  • Vancomycin is therefore unable to bind and inhibit transpeptidation during peptidoglycan remodelling/synthesis
    *
41
Q

How can mycobacterium develop reisstance to isoniazid?

A
  • Mutation in the gene katG encoding catalase-peroxidase that renders the target site insensitive
  • Prevents conversion of isoniazid prodrug to the active metabolite
    • Active metabolite blocks fatty acid synthase and prevents inhibition of cell wall mycolic acid synthesis
    • Target site modification
42
Q

Which are drugs are commonly affected by resistance via porins? How does this lead to resistance?

A
  • Porin = transmembrane proteins that form an auqoeus channel and facilitate diffusion of compounds between the bacterial cell and extracellular medium
  • Examples
    • Penicillin
    • Erthryocin
      • Macrolides
    • Gentamycin
      • Aminoglycosides
  • Reduction in membrane porin density reduces antibiotic influx into the bacterium
43
Q

What has been the predominant way for tetracycline resistance?

A
  • Class A tetracycline efflux pumps
    • High prevalence in Enterobacteriae
    • Encoded by tet(A) genes
  • Expression of membrane transporter proteins that promote efflux
44
Q

Describe strains of bacteria that have developed multi-drug efflux pumps (MDEPs).

A
  • Multi-drug efflux pumps = broad specficity and thus extrude a number of different AB substrates
  • Antibiotics extruded
    • Tetracyclines
    • Sulfonamides
    • Quinolines
  • Bacteria
    • MRSA
      • Methicilin-resistant staphylococcus aureus
    • VRE
      • Vancomycin-resistant enterococcus
45
Q

Define biofilm formation and its underlying mechanisms

A
  • Biofilm = structural consortium of bacteria embedded in a self-produced polymer matrix consisting of:
    1. ​​Polysaccharide
    2. Protein
    3. DNA
  • ​Function
    • ​Promote bacterial survival and result in chornic infection
      • Increased antibacterial tolerance
      • Resistant phagocytosis
  • How it leads to antibiotic rsistance
    1. Gradient of oxygen and nutrients from top to bottom resulting in slower bacterial growth at the bottom and is thought these slower growing bacteria confer AB tolerance
    2. Biofilms associated with higher mutation rates
    3. Normal mechanisms (plasmids, sex pili & conjugation bridges)
    4. Physical inhibition of antibiotics
    5. Quorum sensing
      • Mechanism by which bacteria can sense cell population and modify their gene expression to those that will be most advantageous
      • Uses autoinducers / pheromones
  • Targeting
    • Enzymes that destroy biofilm and AB to mediate entry
    • Quorum sensing inhibitors
46
Q

Describe natural selection in antibiotic resistance

A
  • Driving force behind the emergnece of antibiotic resistant straisn of bacteria by natural selection
  • Selection pressures provoke an increase in the numbers of ABR bacteria
47
Q

Outline the factors/policies that accelerate antibiotic resistance

A
  • Overprescription
    • ​Antibiotics prescribed unncessarily either out of uncertainty of the casue of a disease presentation or pressure from patietns, or for longer courses than required
    • Empirical use of broad spectrum ABs
  • ​Non-prescriptive sale
    • ​Many ABs can be purchased over the counter (OTC)
      • ​Promoting inappoprriate and indiscriminate AB self-administration
  • ​​Non-compliance
    • ​Patients who fail to complet a full course of antibiotic therapy more likely to promote survival of resistant bacteria
    • Directly observed therapy (DOT)
      • ​Healthcare workers observe patiient taking the medication
    • Problem for long course ssuch as TB where patietns may miss dose
  • ​Agriculture
    • ​Food producers fortify animal feed with ABs to prevent infectiosn and promote growth
  • ​Sub-optimal dose
    • ​Kills only a few pathogens, those mutate and replicate for persistent infection

​

48
Q

Describe the role of hospitals in contributing to MRSA

A
  • Background
    • SA = gram psotive, non-motile bacteria, catalase positive, coagulase positive
    • Found in human microbiata as a commensal of the nasal mucosa
    • Enters into the blood/underlying tissue
      • Cutaneous or mucosal barriers broken due to wounds/surgical intervention/catheters
  • Spread between SA
    • Horizontal gene transferof staphyococus chromosome casette (various genes involved)
      • MecA
        • Codes for PBP-2a
        • Beta-lactam resistance
          • Beta-lactams inhibit 4 other PBPs (1, 2, 3 and 4)
  • ​​​​​Spread in hospitals due to:
    • People predisposed to infection
      • Invasive procedures
      • Immune compromised
    • High selection
    • Frequent contact between people
49
Q

How is resistance to chloramphenicol achieved?

A
  • Plasmid determined enzymes
50
Q

How is resistance to streptomyocin achieved?

A
  • Chromosomally-determined alteration of target site
51
Q

Outline methods to combat antibacterial resistance

A
  • Understand the disease process
    • ​Host pathogen interactions
    • Toxin mediated disease
    • Bacterial capsules
  • ​Use the genome sequence
    • ​Work backwards from DNA to see bacterial proteins/antigens
    • Know antigenic variation prcisely
    • Target antigens in combination
  • ​Understand immunity
    • ​Isolate memory cells
    • Screen them for functional antibodies
    • Clone the sequence
    • Transfect into cells
    • Understand complement interactions with bacteria
  1. ​Combination therapy
    • ​Sulfamethazole and trimethoprim
  2. ​Reduced bacterial spread ​
  3. Developing new antibiotics
    • Linezolid (different to isoniazid)
      • Prevents formation of 30s, 50s and tRNA complex
      • Gram positve bacteria specific
      • May be more effective than vancomycin for treating MRSA
52
Q

What are the problems associated with combatting antibiotic resistance?

A
  • Use of current antibiotics
    • Shift in attitude towards infectious diseases
  • Drug devleopment
    • ​Not attractive for drug companies as new drugs would be rationed so would mean lower profits
    • Long process to develop
      • ​15 years
    • ​Expensive
    • Limited number of mechansisms that ABs can act on
      • If they evolve then it is harder to develop
  • Specialised diagnosis (Longitude Prize)
    • ​Idea to have a device that can be used in a clinic to quickly identify the cause of infection soa narrower spectrum AB can be used
    • £10 million prize fund for a research time that can develop point of care diagnosis for testing the cause of infection
    • Must be:
      • ​Accurate
      • Rapid
      • Affordable
      • Easy to use
    • ​Potnetial one is transcriptome
      • ​Host resposne to bacterial/viral infections is different
      • Take mRNA of blood, sequence it and look for differneces in blood between bacterial adn viral
      • 2 genes that are upregulated in bacteria compared to virus
53
Q

Statistic on global prevalence of sepsis

A
  • The 11 million deaths from sepsis account for one in five of all deaths around the world.

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