Center for Integrated Protein Science Department of Chemistry, Technische Universität München, Lichtenbergstraße 4, 85747, Garching, Germany.
Division of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.
Angew Chem Int Ed Engl. 2018 Jan 2;57(1):348-353. doi: 10.1002/anie.201709365. Epub 2017 Dec 5.
The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones, we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation through enzyme assays and customized C metabolite profiling showed that both targets are functionally impaired by the β-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold, thus demonstrating the therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.
抗生素耐药性的传播是治疗结核分枝杆菌感染的主要挑战。此外，药物的疗效通常受到菌膜通透性有限的限制。一线抗生素抑制菌膜生物合成，导致细胞迅速死亡。受此机制的启发，我们利用β-内酰胺类作为潜在的类异戊二烯酸模拟物，来阻断参与其生物合成的丝氨酸水解酶。在一系列β-内酰胺类化合物中，我们发现了一种具有强大抗分枝杆菌和杀菌活性的化合物。使用炔基探针的化学蛋白质组学鉴定出 Pks13 和 Ag85 丝氨酸水解酶是主要的靶标。通过酶测定和定制的 C 代谢物分析进行验证表明，这两种靶标都被β-内酰胺类化合物功能性地抑制。与一线抗生素联合使用可使抗结核分枝杆菌的活性增强 100 多倍，从而证明了靶向菌膜生物合成丝氨酸水解酶的治疗潜力。
