法国巴斯德研究所Didier Mazel研究小组取得一项新突破。他们揭示了工程毒素-内含肽抗菌剂可以选择性地靶向和杀死混合菌群中的耐药细菌。 这一研究成果于2019年4月15日发表在国际顶尖学术期刊《自然—生物技术》上。

该研究团队设计了一种毒素，该毒素首先通过内含肽被分解，然后通过结合在混合菌群中进行传递。该毒素-内含肽抗菌药物只在含有特定转录因子的细菌中被激活。研究人员利用该抗菌药物应用于特异性靶向并杀死混合菌群中的耐抗生素霍乱弧菌。研究组发现接受质粒的耐药霍乱弧菌100%被杀死。逃逸突变体极其罕见(10^-6-10^-8)。斑马鱼和克氏体线虫幼虫是弧菌的天然宿主，该课题组研究人员通过这两种宿主展示了结合和和特异性杀灭目标细菌的现象。通过内含肽分裂的毒素可以作为针对耐抗生素的病原体的精准抗菌剂的基石。

据悉，在不伤害宿主内有益微生物群成员的情况下，有针对性地杀死致病菌，有望成为一种治疗疾病的策略，并限制与抗菌素相关的菌群失调和抗菌素耐药性的发展。

附：英文原文

Title: Engineered toxin–intein antimicrobials can selectively target and kill antibiotic-resistant bacteria in mixed populations

Author: Rocío López-Igual, Joaquín Bernal-Bayard, Alfonso Rodríguez-Patón, Jean-Marc Ghigo, Didier Mazel

Issue&Volume: Volume 37 Issue 7, July 2019

Abstract: Targeted killing of pathogenic bacteria without harming beneficial members of host microbiota holds promise as a strategy to cure disease and limit both antimicrobial-related dysbiosis and development of antimicrobial resistance. We engineer toxins that are split by inteins and deliver them by conjugation into a mixed population of bacteria. Our toxin–intein antimicrobial is only activated in bacteria that harbor specific transcription factors. We apply our antimicrobial to specifically target and kill antibiotic-resistant Vibrio cholerae present in mixed populations. We find that 100% of antibiotic-resistant V. cholerae receiving the plasmid are killed. Escape mutants were extremely rare (10^-6–10^-8). We show that conjugation and specific killing of targeted bacteria occurs in the microbiota of zebrafish and crustacean larvae, which are natural hosts for Vibrio spp. Toxins split with inteins could form the basis of precision antimicrobials to target pathogens that are antibiotic resistant.

DOI: https://doi.org/10.1038/s41587-019-0105-3

Source: https://www.nature.com/articles/s41587-019-0105-3