Wang Yuchuan, Han Bingjie, Xie Yanxuan, Wang Haibo, Wang Runming, Xia Wei, Li Hongyan, Sun Hongzhe
School of Chemistry , Sun Yat-sen University , Guangzhou , 510275 , P. R. China.
Department of Chemistry , The University of Hong Kong , Hong Kong , P. R. China . Email:
Chem Sci. 2019 May 2;10(24):6099-6106. doi: 10.1039/c9sc01480b. eCollection 2019 Jun 28.
Gallium(iii) has been widely used as a diagnostic and therapeutic agent in clinics for the treatment of various diseases, in particular, Ga-based drugs have been exploited as antimicrobials to combat the crisis of antimicrobial resistance. The therapeutic properties of Ga(iii) are believed to be attributable to its chemical similarity to Fe(iii). However, the molecular mechanisms of action of gallium remain unclear. Herein, by integrating metalloproteomics with metabolomics and transcriptomics, we for the first time identified RpoB and RpoC, two subunits of RNA polymerase, as Ga-binding proteins in . We show that Ga(iii) targets the essential transcription enzyme RNA polymerase to suppress RNA synthesis, resulting in reduced metabolic rates and energy utilization. Significantly, we show that exogenous supplementation of acetate could enhance the antimicrobial activity of Ga(iii), evidenced by the inhibited growth of persister cells and attenuated bacterial virulence. The effectiveness of co-therapy of Ga(iii) and acetate was further validated in mammalian cell and murine skin infection models, which is attributable to enhanced uptake of Ga(iii), and reduced TCA cycle flow and bacterial respiration. Our study provides novel insights into the mechanistic understanding of the antimicrobial activity of Ga(iii) and offers a safe and practical strategy of using metabolites to enhance the efficacy of Ga(iii)-based antimicrobials to fight drug resistance.
镓（III）已在临床上广泛用作诊断和治疗剂，用于治疗各种疾病，特别是，基于镓的药物已被开发用作抗菌剂，以应对抗菌药物耐药性危机。镓（III）的治疗特性被认为归因于其与铁（III）的化学相似性。然而，镓的分子作用机制仍不清楚。在此，通过将金属蛋白质组学与代谢组学和转录组学相结合，我们首次在……中鉴定出RNA聚合酶的两个亚基RpoB和RpoC为镓结合蛋白。我们表明，镓（III）靶向必需的转录酶RNA聚合酶以抑制RNA合成，导致代谢率和能量利用率降低。值得注意的是，我们表明外源补充乙酸盐可以增强镓（III）的抗菌活性，这通过持续存在细胞生长的抑制和细菌毒力的减弱得到证明。镓（III）和乙酸盐联合治疗的有效性在哺乳动物细胞和小鼠皮肤感染模型中得到进一步验证，这归因于镓（III）摄取的增加、三羧酸循环流量的减少和细菌呼吸的降低。我们的研究为镓（III）抗菌活性的作用机制理解提供了新的见解，并提供了一种安全实用的策略，即利用代谢物来增强基于镓（III）的抗菌剂对抗耐药性的功效。
