Chan Alex H Y, Ho Terence C S, Fathoni Imam, Hamid Rawia, Hirsch Anna K H, Saliba Kevin J, Leeper Finian J
Yusuf Hamied Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK
Research School of Biology, The Australian National University Canberra ACT 2601 Australia.
RSC Med Chem. 2024 Apr 2;15(5):1773-1781. doi: 10.1039/d4md00083h. eCollection 2024 May 22.
Most pathogenic bacteria, apicomplexan parasites and plants rely on the methylerythritol phosphate (MEP) pathway to obtain precursors of isoprenoids. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS), a thiamine diphosphate (ThDP)-dependent enzyme, catalyses the first and rate-limiting step of the MEP pathway. Due to its absence in humans, DXPS is considered as an attractive target for the development of anti-infectious agents and herbicides. Ketoclomazone is one of the earliest reported inhibitors of DXPS and antibacterial and herbicidal activities have been documented. This study investigated the activity of ketoclomazone on DXPS from various species, as well as the broader ThDP-dependent enzyme family. To gain further insights into the inhibition, we have prepared analogues of ketoclomazone and evaluated their activity in biochemical and computational studies. Our findings support the potential of ketoclomazone as a selective antibacterial agent.
大多数致病细菌、顶复门寄生虫和植物依靠甲基赤藓糖醇磷酸（MEP）途径来获取类异戊二烯的前体。1-脱氧-D-木酮糖-5-磷酸合酶（DXPS）是一种依赖硫胺素二磷酸（ThDP）的酶，催化MEP途径的第一步也是限速步骤。由于人体中不存在DXPS，它被认为是开发抗感染药物和除草剂的一个有吸引力的靶点。酮咯草酮是最早报道的DXPS抑制剂之一，其抗菌和除草活性已有文献记载。本研究调查了酮咯草酮对不同物种DXPS以及更广泛的依赖ThDP的酶家族的活性。为了进一步深入了解这种抑制作用，我们制备了酮咯草酮的类似物，并在生化和计算研究中评估了它们的活性。我们的研究结果支持了酮咯草酮作为一种选择性抗菌剂的潜力。
