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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.
摘要：
GyrB和ParE是IIA型拓扑异构酶并且在大多数细菌中发现。它的功能对DNA复制至关重要，修复和报废。DNAGyrB和ParE的高度保守的ATP结合亚基在结构上相关，已被认为是开发具有广谱潜力的双靶向抗菌剂的主要候选者。然而,在临床上没有针对GyrB和ParE酶的ATPase催化域的天然产物或小分子抑制剂成功。此外，没有报道这些酶的抑制剂对革兰氏阴性病原体具有广谱抗菌活性。GyrB和ParE的高分辨率晶体结构的可用性使设计具有双重作用机理的许多不同类别的抑制剂成为可能。其中苯并咪唑，苯并噻唑,噻唑并吡啶,咪唑并吡啶唑，吡啶,吲唑,吡唑,咪唑并吡啶,三唑并吡啶,吡咯并嘧啶,嘧啶并吲哚以及相关结构公开于文献中。不幸的是,发现这些抑制剂中的大多数对革兰氏阳性病原体具有活性。在本综述中，我们讨论了新型双靶向ATPase抑制剂的研究。
