Antibacterials & Resistance Flashcards
What are the definitions for the following terms; antibacterial, antibiotic, antimicrobial?
antibacterial - a substance that kills bacteria, or inhibits their growth
antibiotic - substances produced by living organisms capable of destroying or inhibiting the growth of micro-organisms
antimicrobial - a substance that kills microorganisms or inhibits their growth. Includes antivirals, antifungals, and antiparasitics, as well as antibacterials
What is the difference between bactericidal and bacteriostatic antibiotics?
bactericidal: kill bacteria but low concentrations can be bacteriostatic
bacteriostatic: slow bacterial growth or reproduction but high concentrations or combinations can be bactericidal
What is the difference between gram -ve vs gram +ve bacteria in terms of antibiotics resistance?
gram -ve bacteria have two membranes, making them less susceptible to antibiotics
gram +ve bacteria have 1 membrane making it more permeable to antibiotics
Why are cell wall inhibitors effective antibiotics?
- highly selective (no cell wall in mammals)
- disrupt bacterial maintenance of osmotic pressure
- generally more effective against gram positives
- first antibiotics
- generally bactericidal
How do beta lactam cell wall inhibitors work?
NAM and NAG peptides crosslink peptidoglycan in cell wall making a v stable complex
beta lactams prevent this crosslinking, causing significant loss of integrity
crosslinking require DD-transpeptidases, beta-lactams mimic this
How does fosfomycin inhibit the cell wall?
blocks action of phosphoenolpyruvate which converts NAG to NAM –> less crosslinking opportunities
How does cycloserine inhibit the cell wall?
inhibits alanine racemase preventing conversion of L-ala to D-ala –> NAM side chain unable to form
How does bacitracin inhibit the cell wall?
inhibits isoprenylpyrophosphatase which dephosphorylates the lipid carrier molecule Und-PP, preventing its conversion to the active form, Und-P
Und-P serves as a carrier molecule that transports peptidoglycan precursors across the cell membrane during cell wall synthesis.
How do vancomycin and teicoplanin inhibit the cell wall?
vancomycin and teicoplanin are last line of defense antibiotics, saved for serious gram positive infection
vancomycin mimics D-ala and takes its place, preventing NAG-NAM crosslinking
How is synthetic penicillin made and what are the advantages?
- strip side chains from natural penicillin and replace w new ones
- stop synthesis of penicillin early by the fungus, and purify the central beta-lactam ring core
- susceptibility to penicillinases overcome by methicillin, oxacillin
- narrow specificity - overcome by amoxicillin, ampicillin
eg
- cephalosporins
- carbopenems
last line os defense
What is the benefit of beta-lactamase inhibitors?
can be used in conjunction w previous beta lactams to make them effective for sure
prolongs the use of antibiotics that bacteria has become resistant to
What is the action of rifampicin?
inhibition of bacterial DNA-dependent RNA synthesis
high affinity for prokaryotic RNA polymerase
usually bacteriostatic
synthesis blocked by steric clashes w the growing oligonucleotide
inhibits elongation of the transcript
antibiotic ineffective once RNA strand is being read
What is the action of fluoroquinolones?
- DNA synthesis inhibitors
- contain a fluorine atom
- broad spectrum
- potential for human toxicity
- rapidly bactericidal
can be modified to gram +ve and gram -ve or just gram +ve
gyrase: introduces transient break in DNA, to allow uncoiling
- stabilises gyrase-DNA complex so DNA cannot be released and replication is blocked
–> strand broken, leading to cell death
What is the action of metronidazole?
- selectively absorbed by anaerobic bacteria
- reduced by reacting w reduced ferredoxin
- reduced intermediates damage enzymes and from unstable molecules in DNA
can be used to treat bacteria in the gut
What is the action of folic acid synthesis inhibitors?
folic acid enzymes needed for synthesis of amino acids, therefore necessary for bacterial protein synthesis
–> singularly = bacteriostatic
–> in combination = bactericidal
eg sulphonamides, diaminopyrimidines
Why is it important to use antibiotics in combination?
- delays emergence of resistance
- synergy between the two drugs
- individually bacteriostatic, bactericidal in combination
- act in sequential steps in pathway
What are monobactams?
- synthetic
- similar to beta-lactam
- single ring
What is isoniazid?
- effective against mycobacteria
- inhibits mycolic acid synthesis
What is the action of polymyxin B (colistin)?
- disrupts plasma membrane
- real last line of defence
- deemed to toxic in the 70s, brought back in the 2000s
- acts on lipopolysaccharides of gram -ves
- bacteria resistant to this would have changed its membrane structure = no LPS detection by the immune system
What is meant by bypass in the context of antimicrobial resistance?
microbes with mutated genes for antimicrobial resistance can bypass the deleterious effects if they possess a plasmid w the corresponding genes
What ways can bacteria be resistant to beta-lactams?
- production of beta-lactamases, located in the periplasmic space
–> usually plasmid mediated, but can be chromosomal encoded on mobile genetic elements - perturbation of the penicillin binding proteins eg enzyme inhibition or competitive binding
- permeability (influx and efflux)
How can alterations in beta-lactamase expression confer resistance?
- induction
- interference with repressor protein - de-repression
- mutation in repressor gene
What are extended spectrum beta lactamases?
enzymes that can degrade cephalosporins
4 classes: A-D
enzymes that can degrade newer generation beta-lactams can degrade older ones but not vice versa
What is the action of beta lactamases?
binds to certain substrate and cleaves the amide ring making the antibiotic completely ineffective
