Localized pmrB hypermutation drives the evolution of colistin heteroresistance

Colistin has emerged as an important last line of defense for the treatment of infections caused by antibiotic-resistant gram-negative pathogens, but colistin resistance remains poorly understood. Here, we investigate the responses of approximate to 1,000 populations of a multi-drug-resistant (MDR) strain of P. aeruginosa to a high dose of colistin. Colistin exposure causes rapid cell death, but some populations eventually recover due to the growth of sub-populations of heteroresistant cells. Heteroresistance is unstable, and resistance is rapidly lost under culture in colistin-free medium. The evolution of heteroresistance is primarily driven by selection for heteroresistance at two hotspot sites in the PmrAB regulatory system. Localized hypermutation of pmrB generates colistin resistance at 10(3)-10(4) times the background resistance mutation rate (approximate to 2 x 10(-5) per cell division). PmrAB provides resistance to antimicrobial peptides that are involved in host immunity, suggesting that this pathogen may have evolved a highly mutable pmrB as an adaptation to host immunity.

Automated summary

Colistin has become an important option for treating infections caused by antibiotic-resistant gram-negative pathogens, but the mechanism of colistin resistance is not well understood. In this study, exposure to colistin led to rapid cell death, but some populations were able to recover through the growth of sub-populations of heteroresistant cells. Heteroresistance was found to be unstable and quickly lost when cultured without colistin. The evolution of heteroresistance was primarily driven by selection for heteroresistance at two hotspot sites in the PmrAB regulatory system.