Micro - Antibiotics MOAs

antibiotics must be selectively toxic

2 essential requirements...

disrupt structure/process essential for growth/survival of pathogen

cause min harm to host

Several MOAs

breach cell walls

hack into info centres (inhibit DNA rep/RNA synthesis)

disrupt factories (inhibit nucleic acid/protein synthesis)

Cell wall active agents

bacterial cell wall consists of peptidoglycan - prevents lysis

agents disrupt peptidoglycan synthesis (cross-linking)

bactericidal

anti-gram +ve (more peptidoglycan + no outer membrane)

outer membrane surrounding gram -ve cell wall is impermeable to these agents (they're too big)

peptidoglycan sythesis: tetrapeptides crosslinked via transpeptidases (aka PBPs)

b-lactams bind to transpeptidase

glycopeptides bind to side chains (acyl-D-alanyl-D-alanine of NAM residues) - block elongation of peptidoglycan backbone (used for MRSA)

Nucleic acid synthesis inhibitors

prevents bacteria making enzymes that are essential for survival + growth, hence bactericidal

quinolones

inhibit bacterial DNA gyrase in gram -ve

inhibit bacterial topoisomerase IV in gram +ve

both enzymes catalyse reverse supercoiling

enter cells easily via porins - often used to Tx intracellular pathogens

fluoroquinolones have improved spectrum (e.g. ciprofloxacin)

RNA synthesis inhibitor = rifampicin

inhibits RNAP + hence initiation of RNA synthesis

bactericidal

no activity against gram -ve (low uptake as drug is hydrophobic)

Antimetabolites

sulphonamides, trimethoprim, dapsone

bacteria sysnthesise THF (tetrahydrofolate) using a no. of enzymes + incorporate it into DNA nucleotides (precursor)

blocked by these

protein synthesis inhibitors

translation occurs in ribosomes (50S+30S)

tRNA (carries AAs) + mRNA (contains codons) required

aminoglycosides + tetracyclines prevent tRNA binding to 30S

chloramphenicol prevents tRNA binding to 50S

linezolid binds to 50S

macrolides + clindamycin inhibit mRNA @ 50S

others: sodium fusidate , lincosamides

daptomycin

novel

MOA: binds to bacterial membranes + causes rapid depol

inhibits protein + DNA + RNA synthesis

bactericidal

conc dependent

spectrum

gram +ve, MSSA, MRSA, S epidermis, Strep (incl PRSP-pencillin resistant S pneumoniae), enterococcus faecium + faecalis (incl VRE)

inactive against gram -ve aerobes

Future = to search for new targets + approaches

host defence peptides

anti virulence Tx

bacteriophages

pathogen membrane depol

immunoregulatory effects

reduce pathogen's virulence

selectively target infection sites

sortase inhibitors (inhibits pathogen adhesion to host)

siderophore inhibitors (target Fe metabolism - inhibit bacterial growth)

still in preclinical phase (in vitro + animal trials)

naturally occurring

may have v specific host range - targeted tx