Antibiotics Action and Resistance

Antibiotics Action and Resistance

1. Cell Wall Synthesis Inhibitors

   • Beta Lactams
     • Flucloxacillin
     • Amoxicillin
       • + Clavulanic Acid
         • Co-Amoxiclav
         • Beta Lactamase Inhibitor
     • Phenoxymethylpenicillin
     • Action
       • Bacteriocidal
       • Contains Beta Lactam Ring
       • Binds Pencillin Binding proteins and Inhibits them
         • PBP binds D-ala-D-Ala at end of peptidoglycan precursor to crosslink the peptidoglycan and form cell wall at final stage
         • Leads to accumulation of precursor cell wall units and eventual cell lysis
     • Cephalosporins
       • Ist Generation
         • Cefradine
       • 3rd Generation
         • Cefixime
         • Ceftriaxone
         • Cefotaxime
         • Increased gram negative antimicrobial properties
     • Benzylpenicillin
     • Penicillin
     • Ampicillin
     • Resistance
       • Target site
         • Modify existing PBP so lower binding affinity
         • import gene coding resistant PBP
         • synthesis PBP's with low affinity so normal ones blocked but LA can continue to build
       • Access to target site
         • Lose porin to decrease permeability of memb to restrict entry
         • Pump out more with increased efflux pumps
       • Beta Lactamases
         • increase to catalyse hydrolysis of beta lactam ring causing inactivity
   • Glycopeptide
     • Teicoplanin
       • for MRSA
     • Vancomycin
     • Action
       • Bacteriocidal
       • too large to penetrate gram -ve bac
       • Inhibits peptidoglycan synthesis thus interfering with cell wall synthesis
       • Binds d-ala-d-ada at end of pentapeptide chians part of gowing cell wall.
       • Inhibits transglycosylation and prevent incorp of new subunits
     • Resistance
       • Altered glycopeptide target
         • end in d-ala-d lac or d-ala-d-ser
         • VanA, vanB, VanD encode ligase to alter it

2. Protein Synthesis Inhibitors

   • Aminoglycosides
     • Gentamicin
     • Action
       • Bacteriocidal
       • Binds to specific proteins in 30S ribosomal subunit
       • Interferes with binding of fmet-tRNA
         • Prevents formation of initiation complexes from which protein synthesis proceeds
       • Causes misreading of mRNA codons
       • Doesn't penetrate tissues and bone well
     • Resistance
       • Target site
         • Alter 30S ribosomal subunit
       • Access
         • cell wall permeability
         • Energy dependent transport across cytplasmic membrane
       • Produce amnoglycoside modifying enzymes
         • modify to inactivate
   • Tetracyclines
     • Oxytetracycline
     • Doxycycline
     • Tetracycline
     • Action
       • Bacteriostatic
       • Binds small ribosomal subunit
         • prevents aminoacyl tRNA from entering acceptor sites
       • Selective- better uptake by prokaryotic cells
     • Resistance
       • Alter target riboosmal unit
       • Access
         • New cytoplasmic membrane proteins syn th- increased efflux
   • Chloramphenicol
     • Action
       • Bacteriostatic
       • Targets 50s subunit
         • blocks action of peptidyl transferase- prevent peptide formation
     • Resistance
       • Alter ribosome
       • Plasmid mediated enzymatic inactivation
         • Actetyl transferase acetylates drug- fails to bind
   • Macrolides
     • Azithromycin
     • Erythromycin
     • Action
       • Bacteriostatic
       • Binds 23D rRNA in 50A subunit of ribosome
       • Blocks translocation step in prot synth
         • prevents release of tRNA after peptide bond forms
     • Resistance
       • Alter 23S rRNA by methylation of 2 adenine nucleotides inRNA
       • Access
         • Efflux mech
       • Methylase enzyme may be inducible or constitutive
   • Lincosamide
     • Clindamycin
       • Bacteriostatic
       • Blocks ribosomes
         • Binds 50S rRNA of ribosome subunit
       • Aerobic gram +ve NOT enterococci and Anaerobic gram -ve
         • Can't do gram -ve too big to pass membrane
       • SE C.difficle assocaited colitis
   • Fusidic Acid
     • Action
       • Bacteriostatic
       • Forms stable complex with
         • elongation factor EF-G
         • guanosine diphosphate
         • ribosome
       • Only for Staph bac
       • Not active for gram -ve
       • IV SE Jaundice
     • Resistance
       • Altered EF-G target

3. Nucleic Acid Synthesis Inhibitors

   • Quinolones
     • Ciprofloxacin
     • Ofloxacin
     • Action
       • Bacteriocidal
       • Interfere with replication of bacterial chromosome
       • Inhibits bacterial DNA gyrase and topoisomerase IV
         • Gyrase produces and removes supercoils in DNA ahead of the replication fork during replication. Top similarly removes.
     • Resistance
       • Target site alter to affect binding
       • permeability, efflux
       • Acetylation inactivation
   • Metronidazole

4. RNA Polymerase Inhibitors

   • Rifampicin
     • Action
       • Bactericidal
       • Binds DNA dependent RNA polymerase
       • blocks mRNA synthesis
     • Resistance
       • Chromosomal mutations alter RNA polymerase target. Lowered affinity.

5. Folate Synthesis Inhibitors

   • Sulphonamides
     • Sulfamethoxazole
       • + trimethoprim
         • Co-trimoxazole
     • Action
       • Compete with para amino benzoic acid for active site of dihydropteroate synthase
         • DS catalyses reaction in synthesis of tetrahydrofolic acid
           • THFA required to synth purine and pyrimidine nucleic acids
       • Bacteriostatic
     • Resistance
       • Plasmid mediated genes coding for altered DS but unchanged affinity for PABA
   • Trimethoprim
     • Action
       • Bacteriostatic
       • Prevent THFA synth by inhibiting DHFR
     • Resistance
       • Plasmid-encoded DHFR with altered affinity got trimeth allow synth
       • Chromosomally encoded overproduction of DHFR