Structure-based design approaches to cell wall biosynthesis inhibitors.
This review summarizes some of the published attempts to incorporate protein and NMR structures in the design of new antibiotics that specifically target Cell Wall biosynthesis. Most of the steps involved in peptidglycan synthesis have been investigated as potential strategies against cell wall inhibition. Structural information has been most useful in the design of molecules in the Mur enzyme pathway, penicillin binding proteins and lactamases, as well as proteins that are part of the final steps of transglycosylation - in particular, d-Ala-d-Ala ligase. Several unique issues exist in the design of effective antibacterials, such as the significant differences in protein structure between organisms, such as the case of MurB in which a large amino acid loop that occupies the active site of the E. Coli is gone in the Staph aureus enzyme. Additionally, bacterial resistance is an important issue, and in some cases, structural information can be used to understand the source of this resistance. For example, mutations within the d-Ala-d-Ala ligases lead to the inability of Vancomycin antibiotics to bind.
Katz
Alan H
AH
Wyeth-Ayerst Research, Princeton, NJ 08540, USA. KATZA@wyeth.com
Caufield
Craig E
CE
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D001426:Bacterial Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002473:Cell Wall / Q000187:drug effects* / Q000201:enzymology; D015195:Drug Design; D005658:Fungi / Q000187:drug effects* / Q000201:enzymology; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase / Q000037:antagonists & inhibitors; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan / Q000096:biosynthesis*; D010458:Peptidyl Transferases; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D046915:Penicillin-Binding Proteins; D010457:Peptidoglycan; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase; D002267:Muramoylpentapeptide Carboxypeptidase