d-Alanyl:d-alanine ligase inhibitors as antibacterial agents against Staphylococcus aureus: a review.

Abstract

Gram-positive pathogen Staphylococcus aureus is associated with human mortality and morbidity worldwide. Mutants of this pathogen is responsible for life threatening community-associated meticillin-resistant infections. Further, the evolution of multidrug-resistant Staphylococcus aureus strains emphasizes the urgent need to develop novel antibacterial agents. ATP-dependent D-alanyl:D-alanine ligase is essential to produce peptidoglycan of bacterial cells, and its inhibition can lead to bacterial cell death, making it a valuable antibacterial target. D-alanyl-D-alanine ligase is recognized as a validated target for the design and development of novel antibacterial agents to overcome resistance problems. In the past several approaches have been used to develop D-alanyl-D-alanine ligase inhibitors with potent antibacterial activity. Some of these inhibitors, including N-acyl-substituted sulfamides, 1-(2-hydroxybenzoyl)-thiosemicarbazide, benzoylthiosemicarbazide, benzoxazoles and diazenedicarboxamides exhibited significant activity against Staphylococcus aureus. The present findings clearly demonstrate that inhibiting D-alanyl:D-alanine ligase is a viable strategy for the discovery of new antibacterial therapies against Staphylococcus aureus.