Rapid gene mutation drives colistin resistance

The hypermutability of one gene in Pseudomonas aeruginosa was shown to drive resistance to colistin, a discovery that researchers said may help improve their understanding of superbugs’ resistance to the last-resort antibiotic.

Natalia Kapel, PhD, a researcher at the University of Oxford, and colleagues published the study in Cell Reports.

Colistin is widely regarded as “an important last line of defense” for infections caused by multidrug-resistant (MDR) gram-negative pathogens, and “there is a pressing need to understand how bacterial pathogens adapt to colistin treatment,” the researchers wrote.

Exposure to colistin causes rapid cell death in bacteria, according to the researchers, but some populations will recover eventually because of heteroresistant cell subpopulations. Since colistin resistance “remains poorly understood,” Kapel and colleagues analyzed about 1,000 populations of an (MDR) strain of P. aeruginosa and how they respond to a high dose of colistin.

Pseudomonas commonly causes lung infections in hospital patients, according to a press release about the study. The researchers wrote that it has moderate efficacy against P. aeruginosa infections.

After treating the P. aeruginosa populations with colistin, Kapel and colleagues sequenced the genomes to analyze the genetic mutation causing resistance and the speed in which different populations developed resistance.

The bacteria developed resistance “at a much higher rate than expected,” according to the release, but there was hope in the discovery that pathogen populations “quickly lost resistance” once the antibiotic was removed due to the high mutation rate.

“Our work has shown that a gene involved in resistance to a last-resort antibiotic mutates at an incredibly high rate, allowing bacteria to quickly evolve antibiotic resistance,” Craig MacLean, a professor of evolution and microbiology at the University of Oxford, said in the release.

Pseudomonas infections were able to evolve resistance quickly because of a gene — pmrB — mutating at 1,000 times the norm.

“Our research suggests that, for this particular case, selective pressures generated by this gene’s association with the immune system may have driven the evolution of extra-fast mutation rate, that be quickly evolving to make bacteria resistant to antibiotics,” MacLean said in the release.

References:

• Common drug-resistant superbug develops fast resistance to ‘last resort’ antibiotic. https://www.eurekalert.org/news-releases/955140. Published June 7, 2022. Accessed Jun 20, 2022.
• Kapel, N, et al. Cell Reports. 2022;doi:10.1016/j.celrep.2022.110929