In the ever-growing antibiotic resistance crisis, even rates of last-resort antibiotic infections are rising.
Colistin is a last-resort antibiotic used when other treatments fail, but rates of colistin-resistant infections are increasing, putting people at even greater risk and increasing the urgency for new therapeutic approaches.
In a new study out of China, lab and animal studies point to a promising way to resensitize pathogens to colistin. In recent years, researchers have tried to do this by combining the antibiotic with nano materials or other drugs. Metabolites have shown some promise, but senior author Guo-Bao Tian, a microbiologist at Sun Yat-sen University’s Zhongshan School of Medicine, turned to animo acids.
Tian and his collaborators chose L-arginine because earlier studies showed it could enhance an antibiotic’s efficacy in resistant infections. The combination quickly and effectively killed strains of E.coli carrying the mcr-1 gene—which drives colistin resistance—while either compound alone showed minimal antibacterial activity.
The team then tested the combination in mice infected with a colistin-resistant strain of E. coli in the peritoneum, the thin tissue covering internal organs. According to the study results, after 72 hours, 80% of mice treated with colistin and L-arginine survived, compared with 40% treated with colistin alone and 0% treated with L-arginine alone. Mice receiving the combination also cleared more bacteria from major organs. Imaging with scanning electron microscopes showed changes in the size and structure of the bacteria, including alterations to the cell membrane.
Transcriptome sequencing then helped reveal how the pair works. The combination alters the cell membrane, allowing colistin to move inside, and that influx triggers production of reactive oxygen species that kill the bacterium. The researchers linked the downregulation of certain metabolism-related genes to the way L-arginine amplifies colistin’s membrane-damaging effects.
“This dual-targeted approach represents a rational strategy to overcome colistin resistance,” said Tian.
While the combination needs further testing for safety and efficacy, researchers are optimistic, calling the combination a “readily translatable” way to preserve the benefits of a critical last-resort antibiotic.