Chemoproteomics of an Indole-Based Quinone Epoxide Identifies Druggable Vulnerabilities in Vancomycin-Resistant Staphylococcus aureus

The alarming global
rise in fatalities from multidrug-resistant Staphylococcus
aureus (S. aureus)
infections has underscored a need to develop new therapies to address
this epidemic. Chemoproteomics is valuable in identifying targets
for new drugs in different human diseases including bacterial infections.
Targeting functional cysteines is particularly attractive, as they
serve critical catalytic functions that enable bacterial survival.
Here, we report an indole-based quinone epoxide scaffold with a unique
boat-like conformation that allows steric control in modulating thiol
reactivity. We extensively characterize a lead compound (4a), which potently inhibits clinically derived vancomycin-resistant S. aureus. Leveraging diverse chemoproteomic platforms,
we identify and biochemically validate important transcriptional factors
as potent targets of 4a. Interestingly, each identified
transcriptional factor has a conserved catalytic cysteine residue
that confers antibiotic tolerance to these bacteria. Thus, the chemical
tools and biological targets that we describe here prospect new therapeutic
paradigms in combatting S. aureus infections.

全球耐多药金黄色葡萄球菌（multidrug-resistant Staphylococcus aureus, S. aureus）感染所致死亡人数的惊人增长，凸显了开发新疗法以应对这一传染病疫情的迫切需求。化学蛋白质组学（chemoproteomics）在包括细菌感染在内的多种人类疾病的新药靶点识别中具有重要价值。靶向功能性半胱氨酸尤其具有吸引力，因其可发挥支撑细菌存活的关键催化功能。本研究报道了一种基于吲哚的醌环氧骨架，其独特的船型构象可实现硫醇反应性调控过程中的空间位阻控制。我们对先导化合物（4a）进行了全面表征，该化合物可强效抑制临床分离的耐万古霉素金黄色葡萄球菌。借助多样化的化学蛋白质组学研究平台，我们识别出关键转录因子并通过生化实验验证其为4a的强效作用靶点。值得注意的是，所有已识别的转录因子均带有保守的催化性半胱氨酸残基，该残基可赋予这类细菌抗生素耐受性。因此，本研究中描述的化学工具与生物学靶点，为对抗金黄色葡萄球菌感染提供了全新的治疗范式。