Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, TX, USA.
Science. 2019 Feb 1;363(6426). doi: 10.1126/science.aau8959.
(Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb's cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.
（结核分枝杆菌）是导致人类死亡的主要传染性病原体。脂质的合成对于结核分枝杆菌的细胞壁和毒力至关重要，而脂质的合成依赖于磷酸泛酰巯基乙胺转移酶（PptT），该酶将 4′-磷酸泛酰巯基乙胺（Ppt）从辅酶 A（CoA）转移到各种酰基载体蛋白上。我们发现了一种通过结合并部分抑制 PptT 来杀死结核分枝杆菌的化合物。同一操纵子中编码的另一种酶，磷酸泛酰巯基乙胺水解酶（PptH），可增强该化合物对结核分枝杆菌的杀伤作用，因为它可以逆转 PptT 反应。因此，PptH 的功能丧失突变体表现出抗微生物的耐药性。我们的 PptT 抑制剂共晶结构可能有助于进一步开发针对这一长期以来备受关注的靶标的抗分枝杆菌药物。PptT 和 PptH 的相反反应揭示了辅酶 A 生理学中的一种调节途径。
