Combatting bacterial infections by killing persister cells with mitomycin C
Combatting bacterial infections by killing persister cells with mitomycin C
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DOI：
10.1111/1462-2920.12873
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发表时间：
2015-11-01
影响因子：
5.1
通讯作者：
Wood, Thomas K.
中科院分区：
文献类型：
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作者：
Kwan, Brian W.;Chowdhury, Nityananda;Wood, Thomas K.
持续存在的细胞是一种耐多药的细菌亚群，其导致慢性和难治性临床感染，如囊性纤维化和结核病。Persisters是代谢休眠的，因此它们对所有传统抗生素都具有高度耐受性，这些抗生素主要对活跃生长的细胞有效。在这里，我们证明了FDA批准的抗癌药物丝裂霉素C（MMC）通过一种不依赖生长的机制根除了持续存在的细胞。MMC是被动运输和生物还原激活，导致自发交联的DNA，我们验证在活跃和休眠细胞。我们发现MMC有效地根除了在丰富和基本培养基中以多种不同生长状态（例如，增殖培养物和高度稳健的生物膜培养物）生长的细胞。此外，MMC是广泛的细菌持久性的有效抑制剂，包括大肠杆菌K-12以及致病性大肠杆菌、金黄色葡萄球菌和铜绿假单胞菌。我们还证明了MMC在动物模型和伤口模型中的疗效，证实了MMC对细菌感染的临床适用性。因此，MMC是第一个能够消除持续存在细胞的广谱化合物，值得研究作为治疗真菌感染的新方法。
Persister cells are a multi-drug tolerant subpopulation of bacteria that contribute to chronic and recalcitrant clinical infections such as cystic fibrosis and tuberculosis. Persisters are metabolically dormant, so they are highly tolerant to all traditional antibiotics which are mainly effective against actively growing cells. Here, we show that the FDA-approved anti-cancer drug mitomycin C (MMC) eradicates persister cells through a growth-independent mechanism. MMC is passively transported and bioreductively activated, leading to spontaneous cross-linking of DNA, which we verify in both active and dormant cells. We find MMC effectively eradicates cells grown in numerous different growth states (e.g. planktonic cultures and highly robust biofilm cultures) in both rich and minimal media. Additionally, MMC is a potent bactericide for a broad range of bacterial persisters, including commensal Escherichia coliK-12 as well as pathogenic species of E.coli, Staphylococcus aureus and Pseudomonas aeruginosa. We also demonstrate the efficacy of MMC in an animal model and a wound model, substantiating the clinical applicability of MMC against bacterial infections. Therefore, MMC is the first broad-spectrum compound capable of eliminating persister cells, meriting investigation as a new approach for the treatment of recalcitrant infections.