Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, China.
Department of Laboratory Medicine, The First Hospital of Changsha, Changsha, 410005, Hunan, China.
Cell Mol Life Sci. 2022 Oct 16;79(11):552. doi: 10.1007/s00018-022-04588-5.
Staphylococcus aureus, a common gram-positive pathogenic bacterium, is a main cause of hospital infection. The prevalence rate of methicillin-resistant S. aureus (MRSA) has made its treatment difficult in recent decades. Moreover, S. aureus in the highly tolerant format of biofilm or persister often renders infections refractory. Thus, developing new active compounds against resistant S. aureus is urgently needed. In this study, by a high-throughput screening assay, we identified a small molecule, L007-0069, that exhibited strong and effective bactericidal activity against S. aureus and its high resistance patterns, such as biofilms and persisters, with a low probability of inducing resistance. By molecular dynamics and fluorescent probe analysis, mechanistic studies revealed that the bactericidal activity of L007-0069 was mainly mediated by membrane disruption and metabolic disorder induction. Furthermore, L007-0069 showed effective anti-MRSA effects in vivo in both a wound infection model and a peritonitis-sepsis model, with no detectable toxicity observed at the therapeutic dosage. In conclusion, L007-0069 has the potential to become an alternative for the treatment of highly resistant S. aureus-related infections.
金黄色葡萄球菌是一种常见的革兰氏阳性致病细菌，是医院感染的主要原因。耐甲氧西林金黄色葡萄球菌（MRSA）的流行率使得近几十年来其治疗变得困难。此外，处于生物膜或持续存活状态的高度耐受形式的金黄色葡萄球菌常常使感染变得难治。因此，迫切需要开发针对耐药金黄色葡萄球菌的新型活性化合物。在这项研究中，我们通过高通量筛选实验，鉴定出一种小分子化合物 L007-0069，它对金黄色葡萄球菌及其高耐药模式（如生物膜和持续存活状态）具有强大而有效的杀菌活性，诱导耐药的可能性较低。通过分子动力学和荧光探针分析，机制研究表明，L007-0069 的杀菌活性主要通过破坏细胞膜和诱导代谢紊乱来介导。此外，L007-0069 在创伤感染模型和腹膜炎-败血症模型中均显示出有效的抗 MRSA 作用，在治疗剂量下未观察到毒性。总之，L007-0069 有可能成为治疗高度耐药金黄色葡萄球菌相关感染的一种替代药物。
