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