Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
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DOI：
10.1038/ncomms14414
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发表时间：
2017-03-01
影响因子：
16.6
通讯作者：
Payne RJ
中科院分区：
文献类型：
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作者：
Tran AT;Watson EE;Pujari V;Conroy T;Dowman LJ;Giltrap AM;Pang A;Wong WR;Linington RG;Mahapatra S;Saunders J;Charman SA;West NP;Bugg TD;Tod J;Dowson CG;Roper DI;Crick DC;Britton WJ;Payne RJ
结核病（TB）是造成全球发病率和死亡率巨大的原因，目前的治疗方案依赖于使用已经使用了40多年的药物。由于对这些疗法的广泛耐药性，迫切需要新的药物来控制结核病负担。在此，我们描述了代表有前途的新的结核病药物线索的sansanmycin尿苷肽天然产物的类似物的快速合成。所述化合物在体外和细胞内表现出对结核分枝杆菌（TB的病原体）的有效和选择性抑制。天然产物类似物是Mtb磷酸-MurNAc-五肽转位酶的纳摩尔抑制剂，该酶负责分枝杆菌中脂质I的合成。这项工作奠定了基础的尿苷肽天然产物类似物作为新的结核病候选药物，通过抑制肽聚糖的生物合成的发展。耐药结核病（TB）感染率很高，目前只有很少的治疗选择。在这里，作者报告了天然产物sansanmycin的合成类似物，其靶向分枝杆菌细胞壁生物合成，并代表了改善抗结核治疗的有效线索。
Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis. Drug resistant tuberculosis (TB) infections are emerging at a high rate, with only few therapeutic options currently available. Here, the authors report synthetic analogues of the natural product sansanmycin that target mycobacterial cell wall biosynthesis and represent potent leads for improved anti-TB treatments.