527639
| Question | Answer |
| what are the differences between Gram +ve/-ve bacteria? | |
| what is the structure of the peptidoglycan cell wall | linear molecules cross-linked by short peptides |
| Cell wall synthesis step 1 | synthesis of N-acetyl-Muramic acid: UDP-NAcGlucosamine--(+PEP)-> UDP-NAcMur |
| What blocks step 1 | phosphomycin (similar structure to PEP) alkylates enzyme, deactivating it |
| Cell wall synthesis step 2 | Sequential addition of L-Ala, D-Glu, L-Lys: -D-Glu is gamma linked -non-ribosomal peptide synth -no pharmacological agents target this step |
| Cell wall synthesis step 3 | Addition of D-Ala-D-Ala: -added as dipeptide, not sequential -forms UDP-NAcMur-pentapeptide -this step is a target for antibiotics |
| D-Ala-D-Ala synthesis | L-Ala<-->D-Ala (racemase) D-Ala+D-Ala<-->D-Ala-D-Ala (synthase) -both steps inhibited by cycloserine(oxamycin), structural analog of D-Ala with greater affinity for enzyme (~100x) |
| Cell wall synthesis step 4 | transfer to C55 lipid (v. hydrophobic- transfers across membrane): C55-P+UDP-NAcMur-pentapeptide--(-UDP)-->C55-P-P-NAcMur-pentapeptide -no ATP outside cell, energy stored in phosphates and peptide bonds |
| Cell wall synthesis step 5 | Addition of NAcGln C55-P-P-NAcMur-(pentapeptide)(NAcGln) |
| Cell wall synthesis step 6 | addition of 5 Gly to side chain amino of Lysine -non ribosomal but uses Gly-tRNA |
| Cell wall synthesis step 7 | Transfer of disaccharide unit to existing cell wall -releases C55 lipid carrier -blocked by vancomycin (last resort antibiotic), ristocetin -these bind to the D-Ala-D-Ala end and prevent it from occupying the enzyme active site |
| vancomycin | -contains vancosamine sugar -natural product -binds to substrate not enzyme |
| cell wall synthesis step 8 | recycling of C55-P-P--->C55-P + Pi |
| cell wall synthesis step 9 | cross-linking of linear chains: -terminal Gly bonds with 1st D-Ala, releases terminal D-Ala -energy source for reaction=D-Ala-D-Ala peptide bond -blocked by penicillin |
| general penicillin structure |
Image:
Penicillin-core (image/png)
|
| how does penicillin work | -transpeptidase enzyme cross-links -penicillin occupies active site and forms covalent irreversible binding -also inactivates an inhibitor of autolytic enzymes, leading to lysis of the bacterium |
| types of penicillin | -Penicillin G (benzylpenicillin-original natural product), not acid stable, poor oral F -Penicillin V (phenoxymethyl)- acid stable, orally active -Ampicillin (1-amino benzyl) -Mecillinam (activity vs Gram -ve, reduced Gram +ve actvty) |
| PBP | penicillin binding proteins B-lactam antiBs bind to these before action, selective binding indicates at what point of cws antiB acts |
| types of PBP | PBP1 - transpeptidase PBP2 - shape maintainance PBP3 - septum formation PBP4-6 - control amount of cross-linking and hydrolysis of terminal D-Ala |
| Beta-lactamases | -inactivate beta-lactams by breaking beta lactam ring -clavulanic acid=beta lactamase inhibitor (not all beta-lactamases) |
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