ANTIBACTERIAL AGENTS

ANTIBACTERIAL AGENTS

1. TARGET - PEPTIDOGLYCAN

   • targets for Beta-lactams and vancomycin
   • unique to bacteria
   • loses structural integrity without cross-links
   • peptidoglycan has to be made in bits built outside the cell
     • SYNTHESIS
       • subunits made in the cytoplasm and exported to the periplasm
         • then added to pre-existing peptidoglycan (break it down first to add bits inbetween
           • cross links formed by transpeptidases, remove the terminal D-alanine
             • TRANSPEPTIDASES
               • form cross links
               • remove the terminal D-ala, bond formed between the other D-ala and a diamino acid formed
             • NAM and NAG part of the peptidoglycan
   • PENICILLIN BINDING PROTEINS
     • also called transpeptidases and carboxypeptidases
     • in E.coli PBP2 has role in cel elongation
     • PBP3 causes cross wall formation - inhibit you don't get cell division or septum formation
     • lays down new peptidoglycan at the mid point and forms cross-walls
   • BETA-LACTAM ANTIBIOTICS
     • transpeptidses only in prokaryote cells so targets these
       • binds irreversibly to transpeptidases, prevents synthesis of new peptidoglycan
         • get into the active site where the D-ala-D-ala would normally go, transpeptidase can no longer bind there
           • can't cross link, vulnerable to osmotic lysis
     • penicillin
       • contains a beta-lactam ring, then a 5 membered sulphur containing ring, then variable R group
     • cephalosporin
       • has 5 membered beta-lactam ring
     • only affect growing cells - only stops it making new peptidoglycan, doesn't destroy already made
     • vancomycin
       • binds to terminal D-ala-D-ala
         • prevents cross-linking
       • used for MRSA
       • narrow spectrum

2. TARGET - TRANSLATION

   • Rifampin
     • binds to the beta-subunit of RNA polymerase
   • RNA is a holoenzyme - needs several different enzymes to bind to it
   • inhibits initiation of RNA synthesis
   • does still affect mitochondria and chloroplast (bacterial origin)

3. TARGET - PROTEIN SYNTHESIS

   • macrolides (50s)
     • erythromycin - contains lacto-ring with 12 - 16 carbons
       • just gram positives, some gram negatives (legionella)
       • non-toxic - selective for prokaryotic ribosomes
     • prevent translocation during protein synthesis
       • stop movement of tRNA with growing amino acid chain on it from the acceptor site to the peptidyl site
     • targets 50s subunit
   • tetracyclin (30s)
     • only one thats not selective for prokaryotes
       • but can't get into eukaryotic cells so not accumulated enough to have an effect
     • inhibits binding of aminoacyl tRNA
       • stops it getting into the acceptor site
   • aminoglycosides (30s)
     • misreading of proteins being translated - wrong amino acids incorporated
       • inhibition of binding of EF-G to the ribosome
     • is selective

4. TARGET - NUCLEIC ACIDS

   • topoisomerases control DNA supercoiling - creates tightly twisted regions - difficult for organisms to separate the strands
     • some put in more supercoils, some relax supercoils
       • DNA gyrase introduces negative supercoils
         • holds the two ends together when theres a break and passes one of the strand through
         • DNA covalently bound to gyase so it doesn't uncoil
         • ATP hydrolyses required
     • type II enzymes introduce a double strand break in DNA
   • fluroquinolones - synthetic antimicrobial
     • has fluorine group
     • treats UTI's and anthrax
     • ciprofloxacin
   • quinolone binds to gyrase-DNA complex
     • replication inhibited
       • SOS response
         • cell filamentation
           • chromosomes fall apart

5. TARGET - OUTER MEMBRANE

   • polymixins
     • B and D (colistin)
     • old but now significant because of antibiotics
       • treats multidrug resistant
     • positively charged, associate with negatively charged LPS
       • displaces Mg2+ and Ca2+
       • OM destabilised, leakage and death
     • gram negatives
   • ioniazid
     • treats TB
       • phase 1 - rifampicin, isoniazid, pyrazinamide
         • phase 2 - rifampicin, isoniazid
     • prodrug is activated by mycobacterial enzyme
       • not active - made active by myc enzyme
     • interferes with synthesis of mycolic acids in cell wall