Rapid Evolution of Colistin Resistance in a Bioreactor Model of Infection of Klebsiella pneumoniae

Colistin resistance remains an important antibiotic for the therapeutic management of drug-resistant Klebsiella pneumoniae. Despite the numerous reports of colistin resistance in clinical strains, it remains unclear exactly when and how different mutational events arise resulting in reduced colistin susceptibility. Using a bioreactor model of infection, we modelled the emergence of colistin resistance in a susceptible isolate of K. pneumoniae. Genotypic, phenotypic and mathematical analyses of the antibiotic challenged and un-challenged population indicates that after an initial decline, the population recovers within 24h due to a small number of 'founder cells' which have single point mutations mainly in the regulatory genes encoding crrB and pmrB and whose phenotype exhibits colistin MICs up to 100-fold higher than the parental strain. Our work underlines that development of colistin resistance during treatment of susceptible K. pneumoniae infections is readily achieved having implications for the use of cationic antimicrobial peptides as a monotherapy.

粘菌素（Colistin）仍是治疗耐药性肺炎克雷伯菌（Klebsiella pneumoniae）感染的重要抗生素。尽管临床菌株中已有诸多关于粘菌素耐药性的报道，但不同突变事件究竟于何时、以何种方式发生并导致粘菌素敏感性下降，目前仍不明确。本研究借助感染性生物反应器模型，对易感型肺炎克雷伯菌菌株的粘菌素耐药性出现过程进行了建模分析。通过对经抗生素处理与未处理的菌群开展基因型、表型及数学分析，研究发现菌群在初始数量下降后，可在24小时内通过少量“创始细胞”完成恢复；这类细胞主要在编码crrB与pmrB的调控基因中携带单点突变，其表型对应的粘菌素最低抑菌浓度（MIC）较亲本菌株最高可达100倍。本研究表明，在易感型肺炎克雷伯菌感染的治疗过程中，粘菌素耐药性极易产生，该结果对阳离子抗菌肽的单药使用具有重要启示意义。