Department of Molecular, Cell, and Systems Biology, University of California, Riverside, California, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Adv Wound Care (New Rochelle). 2024 Feb;13(2):53-69. doi: 10.1089/wound.2023.0036. Epub 2023 Aug 14.
is an opportunistic pathogen that can establish chronic infections and form biofilm in wounds. Because the wound environment is largely devoid of oxygen, may rely on anaerobic metabolism, such as nitrate respiration, to survive in wounds. While nitrate reductase (Nar) typically reduces nitrate to nitrite, it can also reduce chlorate to chlorite, which is a toxic oxidizing agent. Therefore, chlorate can act as a prodrug to specifically eradicate hypoxic/anoxic, nitrate-respiring populations, which are often tolerant to conventional antibiotic treatments. Using a diabetic mouse model for chronic wounds, we tested the role that anaerobic nitrate respiration plays in supporting chronic infections. forms biofilm deep within the wound where the environment is anoxic. Daily treatment of -infected wounds with chlorate supported wound healing. Chlorate treatment was as effective as a treatment with ciprofloxacin (a conventional antibiotic that targets both oxic and hypoxic/anoxic populations). Chlorate-treated wounds showed markers of good-quality wound healing, including well-formed granulation tissue, reepithelialization and microvessel development. Loss- and gain-of-function experiments showed that requires nitrate respiration to establish a chronic wound infection and form biofilms. We show that the small molecule chlorate, kills the opportunistic pathogen, , by targeting a form of anaerobic metabolism called nitrate respiration. Chlorate holds promise as a treatment to combat diverse bacterial infections where oxygen is limiting and/or where pathogens grow as biofilms because many other pathogens possess Nar and survive using anaerobic metabolism.
铜绿假单胞菌是一种机会性病原体，能够在伤口中建立慢性感染并形成生物膜。由于伤口环境中缺乏大量氧气，铜绿假单胞菌可能依赖于无氧代谢，如硝酸盐呼吸，来在伤口中存活。虽然硝酸盐还原酶（Nar）通常将硝酸盐还原为亚硝酸盐，但它也可以将氯酸盐还原为亚氯酸盐，亚氯酸盐是一种有毒的氧化剂。因此，氯酸盐可以作为一种前药，专门消灭缺氧/无氧、硝酸盐呼吸的铜绿假单胞菌种群，这些种群通常对常规抗生素治疗具有耐受性。我们使用糖尿病小鼠慢性伤口模型，测试了无氧硝酸盐呼吸在支持慢性铜绿假单胞菌感染中的作用。铜绿假单胞菌在伤口深处形成生物膜，那里的环境是缺氧的。每天用氯酸盐治疗感染的伤口有助于伤口愈合。氯酸盐治疗与环丙沙星（一种针对好氧和缺氧/无氧铜绿假单胞菌种群的常规抗生素）一样有效。氯酸盐处理的伤口显示出良好质量的伤口愈合标志物，包括形成良好的肉芽组织、上皮再形成和微血管发育。缺失和功能获得实验表明，铜绿假单胞菌需要硝酸盐呼吸来建立慢性伤口感染并形成生物膜。我们表明，小分子氯酸盐通过靶向一种称为硝酸盐呼吸的无氧代谢形式来杀死机会性病原体铜绿假单胞菌。氯酸盐有望成为一种治疗方法，用于对抗氧气有限和/或病原体以生物膜形式生长的多种细菌感染，因为许多其他病原体具有 Nar 并通过无氧代谢存活。
