卡尔-斯卡格斯创新药物研究所Case W. McNamara研究小组取得一项新突破。他们揭示了基于SuFEx的抗结核化合物不可逆地抑制Pks13。这一研究成果于2025年7月30日发表在国际顶尖学术期刊《自然》上。

课题组人员提出了一种临床前共价化合物CMX410，它含有氟硫酸芳基（SuFEx）弹头，并独特地靶向Pks13的酰基转移酶结构域，Pks13是细胞壁生物合成的必需酶。CMX410对结核分枝杆菌的药敏和耐药菌株具有同等效力，并在多主题感染模型中有效。通过先前描述的机制，CMX410的抑制是不可逆的：CMX410与Pks13 AT结构域的催化丝氨酸反应，通过形成β-内酰胺迅速且不可逆地使活性位点失活。CMX410对其靶点具有高度选择性，并表现出良好的药理学和安全性，在长达14天的大鼠毒性研究中，高达1000 mg / kg的剂量没有出现不良反应。每天一颗。与现有药物不同的作用方式、所有临床测试分离株的高效、口服生物利用度、药物联合测试中的良好性能以及优越的药理和安全性特性使CMX410成为替代过时的细胞壁生物合成抑制剂（如异烟肼和乙胺丁醇）的有希望的同类候选药物。

据介绍，结核分枝杆菌（Mtb）仍然是世界上最致命的细菌病原体。迫切需要开发缩短治疗时间的新药，以防治广泛存在的多重耐药和广泛耐药结核分枝杆菌。

附：英文原文

Title: SuFEx-based antitubercular compound irreversibly inhibits Pks13

Author: Krieger, Inna V., Sukheja, Paridhi, Yang, Baiyuan, Tang, Su, Selle, Daniel, Woods, Ashley, Engelhart, Curtis, Kumar, Pradeep, Harbut, Michael B., Liu, Dongdong, Tsuda, Brendan, Qin, Bo, Bare, Grant A. L., Li, Gencheng, Chi, Victor, Gambacurta, Julian, Hvizdos, Janine, Reagan, Matthew, Jones, Isabelle L., Massoudi, Lisa M., Woolhiser, Lisa K., Cascioferro, Alessandro, Kundrick, Erica, Singh, Parul, Reiley, William, Ioerger, Thomas R., Kandula, Dilipkumar Reddy, McCabe, Jacob W., Guo, Taijie, Alland, David, Boshoff, Helena I., Schnappinger, Dirk, Robertson, Gregory T., Mdluli, Khisi, Lee, Kyoung-Jin, Dong, Jiajia, Li, Shuangwei, Schultz, Peter G., Joseph, Sean B., Love, Melissa S., Sharpless, K. Barry, Petrassi, H. Michael, Chatterjee, Arnab K., Sacchettini, James C., McNamara, Case W.

Issue&Volume: 2025-07-30

Abstract: Mycobacterium tuberculosis (Mtb) remains the world’s deadliest bacterial pathogen1. There is an urgent medical need to develop new drugs that shorten the treatment duration to combat widespread multi-drug-resistant and extensive-drug-resistant Mtb. Here, we present a preclinical covalent compound, CMX410, that contains an aryl fluorosulfate (SuFEx)2 warhead and uniquely targets the acyltransferase domain of Pks13, an essential enzyme in cell-wall biosynthesis. CMX410 is equipotent against drug-sensitive and drug-resistant strains of Mtb and efficacious in multiple mouse models of infection. Inhibition by CMX410 is irreversible through a previously undescribed mechanism: CMX410 reacts with the catalytic serine of the AT domain of Pks13, rapidly and irreversibly disabling the active site by forming a β-lactam. CMX410 is highly selective for its target and thus demonstrates excellent pharmacological and safety profiles, including no adverse effects in a 14-day rat toxicity study up to 1,000mgkg1 per day. The distinctive mode of action from current drugs, high potency across all tested clinical isolates, oral bioavailability, favourable performance in drug combination testing and superior pharmacological and safety characteristics make CMX410 a promising first-in-class candidate to replace outdated cell-wall biosynthesis inhibitors, such as isoniazid and ethambutol, in tuberculosis regimens.

DOI: 10.1038/s41586-025-09286-3

Source: https://www.nature.com/articles/s41586-025-09286-3