Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations.
Antibiotic-induced accumulation of lipid II synergizes with antimicrobial fatty acids to eradicate bacterial populations.
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DOI：
10.7554/elife.80246
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发表时间：
2023-03-06
期刊：
影响因子：
7.7
通讯作者：
Conlon BP
中科院分区：
文献类型：
--
作者：
Sidders AE;Kedziora KM;Arts M;Daniel JM;de Benedetti S;Beam JE;Bui DT;Parsons JB;Schneider T;Rowe SE;Conlon BP
抗生素耐受性和抗生素耐药性是有效和可靠治疗细菌感染的两个主要障碍。鉴定使耐药和耐受细菌对抗生素杀伤敏感的抗生素佐剂可能导致开发具有改善结果的上级治疗。万古霉素是一种脂质II抑制剂，是治疗耐甲氧西林金黄色葡萄球菌和其他革兰氏阳性细菌感染的一线抗生素。然而，万古霉素的使用导致对万古霉素敏感性降低的细菌菌株的流行率增加。在这里，我们表明，不饱和脂肪酸作为有效的万古霉素佐剂迅速杀死一系列革兰氏阳性菌，包括万古霉素耐受和耐药人群。协同杀菌活性依赖于膜结合细胞壁中间体的积累，其在膜中产生大的流体斑块，导致蛋白质离域、异常间隔形成和膜完整性丧失。我们的研究结果提供了一种天然的治疗选择，增强万古霉素对难治性病原体的活性，其潜在机制可进一步用于开发针对难治性感染的抗菌药物。
Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is a frontline antibiotic for treating methicillin-resistant Staphylococcus aureus and other Gram-positive bacterial infections. However, vancomycin use has led to the increasing prevalence of bacterial strains with reduced susceptibility to vancomycin. Here, we show that unsaturated fatty acids act as potent vancomycin adjuvants to rapidly kill a range of Gram-positive bacteria, including vancomycin-tolerant and resistant populations. The synergistic bactericidal activity relies on the accumulation of membrane-bound cell wall intermediates that generate large fluid patches in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. Our findings provide a natural therapeutic option that enhances vancomycin activity against difficult-to-treat pathogens, and the underlying mechanism may be further exploited to develop antimicrobials that target recalcitrant infection.