Antibiotics MOA Flashcards
Beta-lactams - Penicillin, Cephalosporins, Monobactams, Carbapenems
Peptidoglycan is an essential cell wall polymer made of alternating chains of NAM and NAG which are cross linked.
Beta lactams covalently bind to penicillin binding proteins which make the cross links
This weakens the cell causing water to enter and to lyse the cell
Glycopeptides - Vancomycin, Teicoplanin
Inhibit growth and cross linking of cell wall. Inhibits transglycosylase which produces linear strands of peptidoglycan.
Prevents transfer and addition of muramyl-pentapeptide building blocks
Tetracycline - Tetracycline Tigecycline, Minocycline
Inhibits protein synthesis by binding to the 30s subunit.
Involves a region in the 16s ribosomal RNA region containing the base 892
Aminoacyl tRNA anti codon is spatially proximal to the ribosomal RNA region containing base 1400.
Tetracyclines interfere with binding of the 892-1400 region and blocks tRNA aminoacyl from binding
Macrolides - Erythromycin, Azithromycin, Clarithromycin
Selectively inhibit protein synthesis by binding to the 50s subunit.
Blocks translocation
Macrolide binding causes dissociation of peptidyl tRNA from ribosomes
Bacteriostatic
Aminoglycosides - Gentamycin
Spectinomycin: bactericidal
Binds irreversibly to 30s subunit
Prevents translocation and protein synthesis
May also generate errors in the translation of genetic code and alter membrane permeability
Aminocyclitols
Bind to the 30s subunit and inhibit protein synthesis
Quinolones and fluoroquinolones - Nalidix acid
Norfloxacin
Ofloxacin
Levofloxacin
Ciprofloxacin
Do not bind directly to gyrase A or B
Trap gyrase on DNA as tertiary drug-enzyme-DNA complexes, stabilizing the stranded break in DNA (by gyrase)
Gyrase stimulates binding of quinolone to dsDNA
Gyrase cleaves dsDNA to single stranded regions to constitute for antibiotic binding
Quinolones trap Gyrase and topisomerase 5 in a tertiary enzyme drug complex
Complex blocks transcription and DNA replication
Colostin
Binds to the LPS of gram negative
Disrupts both inner and outer membrane
Bactericidal
Rifamycin
Binds close to the active site of catalytic beta subunits.
Inhibits RNA synthesis by physically preventing RNA products being more than 2-3 nucleotide long.
Only antibiotic to target RNA polymerase
Sulphonamides
Structural analogue of PABA (part of vitamin B and folic acid)
Acts as an alternative substrate for DHPS
In sensitive bacteria, it competes with PABA, reducing folic acid synthesis
Bacteriostatic unless thymine levels are low
Trimethoprim
inhibits dihydrofolate reductase
DHFR reduces dihydrofolic acid to tetrahydrofolic acid
Reduced both folic and nucleic acid synthesis
Nitrofurantoin
Reduced form is highly reactive, acts at membrane level, attacks ribosomal proteins, DNA, respiration and pyruvate metabolism.
Metronidazole
Selectively absorbed by anaerobic bacteria by diffusion. Is then non-enzymatically reduced, generating intermediates that react with cysteine-bearing enzymes→ metabolites are taken up into bacterial DNA and form unstable molecules
Metronidazole
Selectively absorbed by anaerobic bacteria by diffusion. Is then non-enzymatically reduced, generating intermediates that react with cysteine-bearing enzymes→ metabolites are taken up into bacterial DNA and form unstable molecules
Describe how DHFR inhibitors work
DHFR inhibitors block folic acid processing; DHFR is a vital enzyme in the biosynthesis of the nucleoside thymidine.
The only source of thymidine is the folate-mediated addition of a methyl group to deoxyuridine monophosphate.
Dihydrofolate is used to regenerate tetrahydrofolate. However if we inhibit dihydrofolate reductase then we block the cycle stopping the synthesis of thymidine monophosphate which is essential for DNA synthesis.
