Laboratory of Host-Pathogen Biology, The Rockefeller University, New York, New York, USA.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0090422. doi: 10.1128/aac.00904-22. Epub 2022 Aug 3.
Tuberculosis (TB) is the leading cause of death from any bacterial infection, causing 1.5 million deaths worldwide each year. Due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) there have been significant efforts aimed at developing novel drugs to treat TB. One promising drug target in Mtb is the arabinogalactan biosynthetic enzyme DprE1, and there have been over a dozen unique chemical scaffolds identified which inhibit the activity of this protein. Among the most promising lead compounds are the benzothiazinones BTZ043 and PBTZ169, both of which are currently in or have completed phase IIa clinical trials. Due to the potential clinical utility of these drugs, we sought to identify potential synergistic interactions and new mechanisms of resistance using a genome-scale CRISPRi chemical-genetic screen with PBTZ169. We found that knockdown of , the negative regulator of the drug efflux pump, confers resistance to PBTZ169. Mutations in are the most common form of resistance to bedaquiline and there is already abundant evidence of these mutations emerging in bedaquiline-treated patients. We confirmed that mutations from clinical isolates confer low level cross-resistance to BTZ043 and PBTZ169. While it is yet unclear whether mutations would render benzothiazinones ineffective in treating TB, these results highlight the importance of monitoring for clinically prevalent mutations during ongoing BTZ043 and PBTZ169 clinical trials.
结核病（TB）是由细菌感染引起的主要死亡原因，每年导致全球有 150 万人死亡。由于结核分枝杆菌（Mtb）耐药菌株的出现，人们已经做出了巨大努力来开发治疗结核病的新药。Mtb 中阿拉伯半乳聚糖生物合成酶 DprE1 是一个很有前途的药物靶点，已经确定了十几种独特的化学支架可以抑制该蛋白的活性。在最有前途的先导化合物中，有苯并噻嗪酮 BTZ043 和 PBTZ169，这两种药物都处于或已经完成了 IIa 期临床试验。由于这些药物具有潜在的临床应用价值，我们使用 PBTZ169 进行了基于全基因组 CRISPRi 的化学遗传筛选，以确定潜在的协同作用和新的耐药机制。我们发现，下调 ，即药物外排泵的负调节剂，可导致对 PBTZ169 的耐药性。 基因突变是对乙胺丁醇最常见的耐药形式，已有大量证据表明这些突变出现在乙胺丁醇治疗的患者中。我们证实，来自临床分离株的 突变赋予 BTZ043 和 PBTZ169 低水平的交叉耐药性。虽然目前尚不清楚 突变是否会使苯并噻嗪酮类药物在治疗结核病方面无效，但这些结果强调了在正在进行的 BTZ043 和 PBTZ169 临床试验中监测临床常见的 突变的重要性。
