Antibiotics Action and Resistance

Cell Wall Synthesis Inhibitors
1. Beta Lactams
  1. Flucloxacillin
  2. Amoxicillin
    1. + Clavulanic Acid
      1. Co-Amoxiclav
      2. Beta Lactamase Inhibitor
  3. Phenoxymethylpenicillin
  4. Action
    1. Bacteriocidal
    2. Contains Beta Lactam Ring
    3. Binds Pencillin Binding proteins and Inhibits them
      1. PBP binds D-ala-D-Ala at end of peptidoglycan precursor to crosslink the peptidoglycan and form cell wall at final stage
      2. Leads to accumulation of precursor cell wall units and eventual cell lysis
  5. Cephalosporins
    1. Ist Generation
      1. Cefradine
    2. 3rd Generation
      1. Cefixime
      2. Ceftriaxone
      3. Cefotaxime
      4. Increased gram negative antimicrobial properties
  6. Benzylpenicillin
  7. Penicillin
  8. Ampicillin
  9. Resistance
    1. Target site
      1. Modify existing PBP so lower binding affinity
      2. import gene coding resistant PBP
      3. synthesis PBP's with low affinity so normal ones blocked but LA can continue to build
    2. Access to target site
      1. Lose porin to decrease permeability of memb to restrict entry
      2. Pump out more with increased efflux pumps
    3. Beta Lactamases
      1. increase to catalyse hydrolysis of beta lactam ring causing inactivity
2. Glycopeptide
  1. Teicoplanin
    1. for MRSA
  2. Vancomycin
  3. Action
    1. Bacteriocidal
    2. too large to penetrate gram -ve bac
    3. Inhibits peptidoglycan synthesis thus interfering with cell wall synthesis
    4. Binds d-ala-d-ada at end of pentapeptide chians part of gowing cell wall.
    5. Inhibits transglycosylation and prevent incorp of new subunits
  4. Resistance
    1. Altered glycopeptide target
      1. end in d-ala-d lac or d-ala-d-ser
      2. VanA, vanB, VanD encode ligase to alter it
Protein Synthesis Inhibitors
1. Aminoglycosides
  1. Gentamicin
  2. Action
    1. Bacteriocidal
    2. Binds to specific proteins in 30S ribosomal subunit
    3. Interferes with binding of fmet-tRNA
      1. Prevents formation of initiation complexes from which protein synthesis proceeds
    4. Causes misreading of mRNA codons
    5. Doesn't penetrate tissues and bone well
  3. Resistance
    1. Target site
      1. Alter 30S ribosomal subunit
    2. Access
      1. cell wall permeability
      2. Energy dependent transport across cytplasmic membrane
    3. Produce amnoglycoside modifying enzymes
      1. modify to inactivate
2. Tetracyclines
  1. Oxytetracycline
  2. Doxycycline
  3. Tetracycline
  4. Action
    1. Bacteriostatic
    2. Binds small ribosomal subunit
      1. prevents aminoacyl tRNA from entering acceptor sites
    3. Selective- better uptake by prokaryotic cells
  5. Resistance
    1. Alter target riboosmal unit
    2. Access
      1. New cytoplasmic membrane proteins syn th- increased efflux
3. Chloramphenicol
  1. Action
    1. Bacteriostatic
    2. Targets 50s subunit
      1. blocks action of peptidyl transferase- prevent peptide formation
  2. Resistance
    1. Alter ribosome
    2. Plasmid mediated enzymatic inactivation
      1. Actetyl transferase acetylates drug- fails to bind
4. Macrolides
  1. Azithromycin
  2. Erythromycin
  3. Action
    1. Bacteriostatic
    2. Binds 23D rRNA in 50A subunit of ribosome
    3. Blocks translocation step in prot synth
      1. prevents release of tRNA after peptide bond forms
  4. Resistance
    1. Alter 23S rRNA by methylation of 2 adenine nucleotides inRNA
    2. Access
      1. Efflux mech
    3. Methylase enzyme may be inducible or constitutive
5. Lincosamide
  1. Clindamycin
    1. Bacteriostatic
    2. Blocks ribosomes
      1. Binds 50S rRNA of ribosome subunit
    3. Aerobic gram +ve NOT enterococci and Anaerobic gram -ve
      1. Can't do gram -ve too big to pass membrane
    4. SE C.difficle assocaited colitis
6. Fusidic Acid
  1. Action
    1. Bacteriostatic
    2. Forms stable complex with
      1. elongation factor EF-G
      2. guanosine diphosphate
      3. ribosome
    3. Only for Staph bac
    4. Not active for gram -ve
    5. IV SE Jaundice
  2. Resistance
    1. Altered EF-G target
Nucleic Acid Synthesis Inhibitors
1. Quinolones
  1. Ciprofloxacin
  2. Ofloxacin
  3. Action
    1. Bacteriocidal
    2. Interfere with replication of bacterial chromosome
    3. Inhibits bacterial DNA gyrase and topoisomerase IV
      1. Gyrase produces and removes supercoils in DNA ahead of the replication fork during replication. Top similarly removes.
  4. Resistance
    1. Target site alter to affect binding
    2. permeability, efflux
    3. Acetylation inactivation
2. Metronidazole
RNA Polymerase Inhibitors
1. Rifampicin
  1. Action
    1. Bactericidal
    2. Binds DNA dependent RNA polymerase
    3. blocks mRNA synthesis
  2. Resistance
    1. Chromosomal mutations alter RNA polymerase target. Lowered affinity.
Folate Synthesis Inhibitors
1. Sulphonamides
  1. Sulfamethoxazole
    1. + trimethoprim
      1. Co-trimoxazole
  2. Action
    1. Compete with para amino benzoic acid for active site of dihydropteroate synthase
      1. DS catalyses reaction in synthesis of tetrahydrofolic acid
        THFA required to synth purine and pyrimidine nucleic acids
    2. Bacteriostatic
  3. Resistance
    1. Plasmid mediated genes coding for altered DS but unchanged affinity for PABA
2. Trimethoprim
  1. Action
    1. Bacteriostatic
    2. Prevent THFA synth by inhibiting DHFR
  2. Resistance
    1. Plasmid-encoded DHFR with altered affinity got trimeth allow synth
    2. Chromosomally encoded overproduction of DHFR

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Antibiotics Action and Resistance

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