Rapid evolution of colistin resistance in a bioreactor model of infection of Klebsiella pneumoniae

Colistin 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 24 h due to a small number of “founder cells” which have single point mutations mainly in the regulatory genes encoding crrB and pmrB that when mutated results in up to 100-fold reduction in colistin susceptibility. Our work underlines the rapid development of colistin resistance during treatment or exposure of susceptible K. pneumoniae infections having implications for the use of cationic antimicrobial peptides as a monotherapy. A combined microbiological and mathematical approach to study colistin resistance in antibiotic sensitive K. pneumoniae reveals a rapid emergence and selection of genetic variants generated by spontaneous mutations in key regulatory genes.