将代谢增强与质粒扩散耦合实现可编程抗菌控制
Coupling metabolic enhancement to plasmid spread enables programmable antimicrobial control
研究者将选择性杀伤模块与优化后的接合质粒结合，构建出可靶向耐药病原体和临床相关耐药质粒的可编程抗菌平台。他们设计的毒素–内含肽模块能分别在种和菌株水平上选择性作用于志贺菌属、肠道沙门菌及携带耐药质粒 pOXA-48 的细菌。比较可移动质粒与接合质粒后，接合系统的递送效率稳定高出约一个数量级。随后简化广宿主范围质粒 RP4，并引入代谢 fos 位点、IV 型菌毛操纵子或两者组合以增强功能；将抗 pOXA-48 模块整合进这些载体后，可在复杂微生物群落中有效抑制耐药质粒扩散。结果表明递送效率和生态竞争力是此类干预成功的关键决定因素。
来源：Nucleic Acids Research · doi.org
The rise of multidrug-resistant pathogens underscores the need for precise antimicrobial strategies beyond conventional antibiotics. Conjugation-based approaches offer a powerful yet underexploited means of delivering targeted genetic interventions within microbial communities. Here, we combine selective killing modules with optimized conjugative vectors to target antibiotic-resistant pathogens and clinically relevant resistance plasmids. First, we engineered toxin–intein modules, programmable cassettes that restrict toxic activity to specific regulatory contexts. We developed modules targeting Shigella spp., Salmonella enterica, and bacteria carrying the resistance plasmid pOXA-48, demonstrating tunable and selective activity at both species and strain levels. To identify the optimal delivery platform, we compared mobilizable and conjugative plasmids, finding that conjugative systems consistently outperform mobilizable ones by approximately one order of magnitude. We then streamlined the broad-host-range plasmid RP4 and enhanced its functionality by incorporating the metabolic fos locus, a type IV pilus operon or both features combined. Integration of the anti-pOXA-48 module into these vectors enabled effective suppression of resistance plasmid spread in complex microbial communities. Together, these results advance the use of conjugative plasmids as programmable antimicrobial platforms and identify delivery efficiency and ecological competitiveness as key determinants of the success of such interventions.