Si Zhangyong, Sun Yan, Tan Chongyun, Ooi Ying Jie, Li Ming, Raju Cheerlavancha, Shubi Jamal, Gan Yunn-Hwen, Zhu Yabin, Li Peng, Chan-Park Mary B, Pethe Kevin
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 637459, Singapore; Cixi Institute of Biomedical Engineering, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315300, China.
Lee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore.
Biomaterials. 2025 May;316:123003. doi: 10.1016/j.biomaterials.2024.123003. Epub 2024 Dec 12.
The incidence of serious lung infections due to Mycobacterium abscessus, a worrying non-tuberculosis mycobacteria (NTM) species, is rising and has in some countries surpassed tuberculosis. NTM are ubiquitous in the environment and can cause serious lung infections in people who are immunocompromised or have pre-existing lung conditions. M. abscessus is intrinsically resistant to most antibiotics. Current treatments involve combination of three or more repurposed antibiotics with the treatment regimen lasting at least 12 months but producing unsatisfactory success rates of less than 50 %. Herein, we report an alternative strategy using a degradable polymer, specifically main-chain cationic carbonate-imidazolium-derived polymer (MCOP-1). MCOP-1 is a non-toxic agent active in a murine lung infection model. MCOP-1 also exhibits excellent efficacy against multi-drug resistant (MDR) ESKAPE bacteria. MCOP-1 damages bacterial membrane and DNA, and serial passaging does not rapidly elicit resistance. Its carbonate linkage is stable enough to allow MCOP-1 to remain intact for long enough to exert its bactericidal effect but is labile over longer time periods to degrade into non-toxic small molecules. These findings underscore the potential of degradable MCOP-1 as a promising therapeutic antimicrobial agent to address the growing incidence of recalcitrant infections due to M. abscessus and MDR ESKAPE bacteria.
脓肿分枝杆菌是一种令人担忧的非结核分枝杆菌（NTM），由其引起的严重肺部感染的发病率正在上升，在一些国家已超过结核病。NTM在环境中普遍存在，可导致免疫功能低下或已有肺部疾病的人发生严重肺部感染。脓肿分枝杆菌对大多数抗生素具有内在抗性。目前的治疗方法是将三种或更多种重新利用的抗生素联合使用，治疗方案持续至少12个月，但成功率低于50%，不尽人意。在此，我们报告了一种使用可降解聚合物的替代策略，特别是主链阳离子碳酸酯-咪唑衍生聚合物（MCOP-1）。MCOP-1是一种在小鼠肺部感染模型中具有活性的无毒药物。MCOP-1对多重耐药（MDR）ESKAPE细菌也表现出优异的疗效。MCOP-1会破坏细菌膜和DNA，连续传代不会迅速产生抗性。其碳酸酯键足够稳定，使MCOP-1能够长时间保持完整以发挥其杀菌作用，但在较长时间内不稳定，会降解为无毒小分子。这些发现强调了可降解的MCOP-1作为一种有前景的治疗性抗菌剂的潜力，以应对由脓肿分枝杆菌和多重耐药ESKAPE细菌引起的顽固性感染发病率不断上升的问题。
