A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans–MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

中文翻译：

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一类新的合成类视黄醇抗生素可有效对抗细菌持久性

治疗金黄色葡萄球菌感染的一个挑战是耐甲氧西林金黄色葡萄球菌 (MRSA) 菌株的高流行率以及非生长、休眠的“持续”亚群的形成，这些亚群对抗生素表现出高水平的耐受性，并在慢性或复发性感染。由于常规抗生素在治疗由此类细菌引起的感染方面无效，因此迫切需要新型抗菌疗法。在这里，我们使用秀丽隐杆线虫-MRSA 感染筛选来鉴定两种合成类视黄醇，CD437 和 CD1530，它们通过破坏脂质双层杀死生长和持久的 MRSA 细胞。CD437 和 CD1530 表现出高杀伤率、与庆大霉素的协同作用以及低抗性选择概率。全原子分子动力学模拟表明，类视黄醇渗透和嵌入脂质双层的能力与其杀菌能力相关。发现 CD437 的类似物保留抗持久活性并显示出改善的细胞毒性特征。CD437 和这种类似物，单独或与庆大霉素组合，在慢性 MRSA 感染的小鼠模型中表现出相当大的功效。随着进一步的发展和优化，合成类视黄醇有可能成为一类新的抗菌药物，用于治疗目前难以治愈的革兰氏阳性细菌感染。CD437 和这种类似物，单独或与庆大霉素组合，在慢性 MRSA 感染的小鼠模型中表现出相当大的功效。随着进一步的发展和优化，合成类视黄醇有可能成为一类新的抗菌药物，用于治疗目前难以治愈的革兰氏阳性细菌感染。CD437 和这种类似物，单独或与庆大霉素组合，在慢性 MRSA 感染的小鼠模型中表现出相当大的功效。随着进一步的发展和优化，合成类视黄醇有可能成为一类新的抗菌药物，用于治疗目前难以治愈的革兰氏阳性细菌感染。