Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 637371, Singapore.
J Mater Chem B. 2021 Apr 14;9(14):3136-3142. doi: 10.1039/d0tb02568b. Epub 2021 Mar 3.
Antibiotic vancomycin (Van) is often used as the drug of last resort to treat methicillin resistant Staphylococcus aureus. Due to the emergence of Van-resistant microbes, it is necessary to continuously design strategies to increase the efficacy of Van against resistant cells. In this study, an efficient method of bio-conjugating Van to bacteria is proposed using near-infrared (NIR)-light activation. A Nd-sensitized upconversion nanocrystal (UCNC) decorated with toluidine blue O (TB) on its surface undergoes upconverted energy transfer from the UCNC to TB when excited by 808 nm light. The photoexcited TB then catalyses the conversion of the dihydrotetrazine (dHTz) moiety in a Van-dHTz conjugate system to tetrazine which undergoes an efficient inverse electron demand Diels-Alder reaction with prior attached norbornene molecules on bacterial cell walls. The enhanced affinity of Van to bacteria by covalent bonding improves the activity of the drug against drug-resistant Enterococci, and the MIC is reduced by 6- to 7-fold as compared to neat Van. We demonstrate that the mode of action is due to increased inhibition of peptidoglycan cell wall biosynthesis. The findings in this study demonstrate that on-demand NIR-light activated bioorthogonal conjugation of Van to microbes is a viable alternative treatment in combating drug-resistant bacteria.
抗生素万古霉素（Van）常被用作治疗耐甲氧西林金黄色葡萄球菌的最后手段。由于耐万古霉素微生物的出现，有必要不断设计策略来提高万古霉素对耐药细胞的疗效。在这项研究中，提出了一种利用近红外（NIR）光激活将万古霉素与细菌偶联的有效方法。表面修饰有甲苯胺蓝 O（TB）的 Nd 敏化上转换纳米晶体（UCNC）在 808nm 光激发下，从 UCNC 到 TB 发生上转换能量转移。光激发的 TB 然后催化二氢四嗪（dHTz）部分在万古霉素-dHTz 缀合物系统中转化为四嗪，四嗪与细菌细胞壁上先前附着的降冰片烯分子发生高效的逆电子需求 Diels-Alder 反应。万古霉素与细菌通过共价键的结合增强了对细菌的亲和力，从而提高了药物对耐药肠球菌的活性，与纯万古霉素相比，MIC 降低了 6 至 7 倍。我们证明这种作用模式是由于肽聚糖细胞壁生物合成的抑制增强所致。本研究结果表明，按需 NIR 光激活的生物正交万古霉素与微生物偶联是一种可行的替代治疗方法，可用于对抗耐药细菌。
