Guy Collette S, Tichauer Esther, Kay Gemma L, Phillips Daniel J, Bailey Trisha L, Harrison James, Furze Christopher M, Millard Andrew D, Gibson Matthew I, Pallen Mark J, Fullam Elizabeth
School of Life Sciences, University of Warwick, Coventry, UK.
Department of Chemistry, University of Warwick, Coventry, UK.
Br J Pharmacol. 2017 Jul;174(14):2183-2193. doi: 10.1111/bph.13744. Epub 2017 Mar 23.
Tuberculosis (TB) remains a major global health threat and is now the leading cause of death from a single infectious agent worldwide. The current TB drug regimen is inadequate, and new anti-tubercular agents are urgently required to be able to successfully combat the increasing prevalence of drug-resistant TB. The purpose of this study was to investigate a piperidinol compound derivative that is highly active against the Mycobacterium tuberculosis bacillus.
The antibacterial properties of the piperidinol compound and its corresponding bis-Mannich base analogue were evaluated against M. smegmatis and Gram-negative organisms. Cytotoxicity studies were undertaken in order to determine the selectivity index for these compounds. Spontaneous resistant mutants of M. smegmatis were generated against the piperidinol and corresponding bis-Mannich base lead derivatives and whole genome sequencing employed to determine the genetic modifications that lead to selection pressure in the presence of these compounds.
The piperidinol and the bis-Mannich base analogue were found to be selective for mycobacteria and rapidly kill this organism with a cytotoxicity selectivity index for mycobacteria of >30-fold. Whole genome sequencing of M. smegmatis strains resistant to the lead compounds led to the identification of a number of single nucleotide polymorphisms indicating multiple targets.
Our results indicate that the piperidinol moiety represents an attractive compound class in the pursuit of novel anti-tubercular agents.
This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.
结核病仍然是全球主要的健康威胁，目前是全球单一感染源导致死亡的首要原因。当前的结核病药物治疗方案并不充分，迫切需要新的抗结核药物来成功应对耐药结核病日益增加的流行情况。本研究的目的是调查一种对结核分枝杆菌具有高活性的哌啶醇化合物衍生物。
评估了哌啶醇化合物及其相应的双曼尼希碱类似物对耻垢分枝杆菌和革兰氏阴性菌的抗菌特性。进行了细胞毒性研究以确定这些化合物的选择性指数。针对哌啶醇和相应的双曼尼希碱先导衍生物产生了耻垢分枝杆菌的自发耐药突变体，并采用全基因组测序来确定在这些化合物存在下导致选择压力的基因修饰。
发现哌啶醇和双曼尼希碱类似物对分枝杆菌具有选择性，并能迅速杀死该菌，对分枝杆菌的细胞毒性选择性指数大于30倍。对耐先导化合物的耻垢分枝杆菌菌株进行全基因组测序，导致鉴定出一些单核苷酸多态性，表明存在多个靶点。
我们的结果表明，在寻找新型抗结核药物方面，哌啶醇部分代表了一类有吸引力的化合物。
本文是关于微生物药物代谢与抗生素耐药性主题板块的一部分。若要查看该板块的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc。
