Amino acid restores power to last-resort antibiotics

Worldwide, antibiotic resistance is associated with millions of deaths every year, and the World Health Organization warns that the number of resistant infections is rising. Colistin is a last-resort antibiotic used when other treatments fail, but rates of colistin-resistant infections are rising as well, putting people at even greater risk and increasing the urgency for new therapeutic approaches.

Recent findings from lab and animal studies point to a promising way to resensitize pathogens to the antibiotic. This week in Microbiology Spectrum, researchers in China reported that combining colistin with L-arginine, an amino acid, restored sensitivity to the drug in bacteria with colistin-resistant genes. The combination changes the cell membrane, allowing colistin to move inside. This influx triggers the intracellular production of reactive oxidative species, which kill the bacterium. In experiments on mice, the combination effectively treated infections by colistin-resistant pathogens.

This dual-targeted approach represents a rational strategy to overcome colistin resistance."

Guo-Bao Tian, Ph.D, senior author, microbiologist, Sun Yat-sen University's Zhongshan School of Medicine

Colistin was first approved in 1959 for use in life-threatening infections caused by Gram-negative bacteria, but was widely avoided due to high toxicity and severe side effects. The emergence of superbugs, pathogenic bacteria resistant to potent antibiotics, in the 1990s led to increased use of the drug as a last-resort therapeutic. Complicating matters, genes that confer colistin resistance spread via small circular bits of DNA called plasmids that bacteria easily share. 

In recent years, researchers have probed diverse strategies for resensitizing bacteria to colistin, combining the antibiotic with nano materials or other drugs, for example. Metabolites, which are produced by the body during metabolism, show some antibiotic activity and have been studied as potential boosters because of how they remodel interactions between the pathogens and the antibiotic. Amino acids, however, have received less attention, said Tian. 

Tian and his collaborators focused on L-arginine, an amino acid that in previous studies has been shown to enhance the efficacy of an antibiotic in resistant infections. They found that the combination effectively and quickly killed strains of Escherichia coli with the mcr-1 gene, which drives resistance in colistin-resistant microbes. L-arginine and colistin when administered alone showed minimal antibacterial activity. 

Those findings led them to test the effect on mice infected with a colistin-resistant strain of E. coli in the peritoneum, the thin tissue that covers internal organs. After 72 hours, the survival rate of mice treated with colistin and L-arginine was 80%-much higher than the rate for those treated with colistin alone (40%) or L-arginine alone (0%). Further analysis showed that mice treated with the combination had also cleared more pathogenic bacteria in major organs. Observations made with scanning electron microscopes and other imaging methods revealed changes in the size and structure of the bacteria, including alterations to the cell membrane. 

The researchers then used transcriptome sequencing to explore the mechanism by which the drug combination works. They connected the downregulation of certain genes related to metabolism to the way that L-arginine amplifies the membrane-damaging effects of colistin. 

The findings point to membrane disruption by the drug combination as a potential therapeutic. However, Tian cautions that it requires further testing to ensure safety and efficacy before it can be harnessed to help people, and that the colistin-resistant bacteria used in the experiment may not represent the full range of strains that cause resistant infections. 

But the researchers are optimistic, calling the combination a "readily translatable" way to preserve the benefits of a critical last-resort antibiotic.