Wellman Center for Photomedicine, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA.
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P. R. China.
Sci Transl Med. 2021 Jan 6;13(575). doi: 10.1126/scitranslmed.aba3571.
Development of alternatives to antibiotics is one of the top priorities in the battle against multidrug-resistant (MDR) bacterial infections. Here, we report that two naturally occurring nonantibiotic modalities, blue light and phytochemical carvacrol, synergistically kill an array of bacteria including their planktonic forms, mature biofilms, and persisters, irrespective of their antibiotic susceptibility. Combination but not single treatment completely or substantially cured acute and established biofilm-associated and methicillin-resistant infections of full thickness murine third-degree burn wounds and rescued mice from lethal skin wound infections. The combined therapy diminished bacterial colony-forming units as high as 7.5 log within 30 min and introduced few adverse events in the survival of cocultured mammalian cells, wound healing, or host DNA. Mechanistic studies revealed that carvacrol was photocatalytically oxidized into a series of photoreactive substrates that underwent photolysis or additional photosensitization reactions in response to the same blue light, forming two autoxidation cycles that interacted with each other resulting in robust generation of cytotoxic reactive oxygen species. This phototoxic reaction took place exclusively in bacteria, initiated by blue light excitation of endogenous porphyrin-like molecules abundantly produced in bacteria compared with mammalian cells. Moreover, no bacterial resistance developed to the combined treatment after 20 successive passages. This highly selective phototoxic reaction confers a unique strategy to combat the growing threat of MDR bacteria.
开发抗生素替代品是对抗多药耐药（MDR）细菌感染的首要任务之一。在这里，我们报告了两种天然存在的非抗生素方式，蓝光和植物化学物质香芹酚，协同杀死了一系列细菌，包括它们的浮游形式、成熟的生物膜和持久菌，而不管它们的抗生素敏感性如何。组合治疗而不是单一治疗完全或基本上治愈了急性和已建立的生物膜相关的以及耐甲氧西林的全层三度烧伤小鼠创面感染，并从致命的皮肤创面感染中拯救了小鼠。联合治疗在 30 分钟内将细菌菌落形成单位减少了高达 7.5 个对数级，并且在共培养的哺乳动物细胞的存活、伤口愈合或宿主 DNA 中引入的不良事件很少。机制研究表明，香芹酚被光催化氧化成一系列光反应性底物，这些底物在相同的蓝光下发生光解或额外的光敏化反应，形成两个相互作用的自氧化循环，导致细胞毒性活性氧的大量生成。这种光毒性反应仅在细菌中发生，由细菌中大量产生的内源性卟啉样分子在蓝光激发下引发，而哺乳动物细胞中则不会产生这种反应。此外，在经过 20 次连续传代后，细菌对联合治疗没有产生耐药性。这种高度选择性的光毒性反应为对抗日益严重的 MDR 细菌威胁提供了一种独特的策略。
