Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: A review

Abstract

GyrB and ParE are type IIA topoisomerases and found in most bacteria. Its function is vital for DNA replication, repair and decatenation. The highly conserved ATP-binding subunits of DNA GyrB and ParE are structurally related and have been recognized as prime candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, no natural product or small molecule inhibitors targeting ATPase catalytic domain of both GyrB and ParE enzymes have succeeded in the clinic. Moreover, no inhibitors of these enzymes with broad-spectrum antibacterial activity against Gram-negative pathogens have been reported. Availability of high resolution crystal structures of GyrB and ParE made it possible for the design of many different classes of inhibitors with dual mechanism of action. Among them benzimidazoles, benzothiazoles, thiazolopyridines, imidiazopyridazoles, pyridines, indazoles, pyrazoles, imidazopyridines, triazolopyridines, pyrrolopyrimidines, pyrimidoindoles as well as related structures are disclosed in literatures. Unfortunately most of these inhibitors are found to be active against Gram-positive pathogens. In the present review we discuss about studies on novel dual targeting ATPase inhibitors.

Keywords: ATPase inhibitors; GyrB; ParE; Pyrrolopyrimidines.