Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Furans/pharmacology , Peptidoglycan/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacteria/metabolism , Furans/chemical synthesis , Furans/chemistry , Microbial Sensitivity Tests , Models, Molecular , Peptidoglycan/biosynthesisABSTRACT
Pulvinones were synthesized (>180) in arrays and evaluated as inhibitors of early stage cell wall biosynthesis enzymes MurA-MurD. Several pulvinones inhibited Mur enzymes with IC(50)'s in the 1-10 microg/mL range and demonstrated antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphyloccus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae.
Subject(s)
Carboxylic Acids/chemical synthesis , Lactones/chemical synthesis , Streptococcus pneumoniae/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Cell Wall/drug effects , Cell Wall/metabolism , Drug Resistance, Bacterial , Enterococcus faecalis/metabolism , Inhibitory Concentration 50 , Methicillin/pharmacology , Microbial Sensitivity Tests , Models, Chemical , Penicillins/pharmacology , Staphylococcus aureus/metabolism , Vancomycin/pharmacologyABSTRACT
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.
