Multi-drug resistant (MDR) Gram-negative bacterial infections present an enormous ongoing challenge to public health. Colistin, a polymyxin antibiotic with noted renal toxicity, is now considered an antibiotic of last resort for the treatment of these infections. With the resurgence in colistin use, colistin-resistant isolates are now becoming more common, especially with the spread of the plasmid-borne mcr-1 gene. To combat the growing threat of colistin-resistance, we initiated a research program to identify small molecules, termed antibiotic adjuvants, that modulate the activity of colistin against MDR Gram-negative pathogens. We have identified molecules that lower the minimum inhibitory concentration (MIC) of colistin up to 2048-fold against both colistin-sensitive and colistin-resistant bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli). Mechanistic studies have shown that our lead compound binds the response regulator PmrA in A. baumannii, downregulates the pmrCAB operon, and reverses lipid A modification. As colistin toxicity is dose dependent, the potential of these compounds to lower dosages for the treatment of MDR Gram-negative bacteria could thereby mitigate toxicity. In the case of colistin-resistant bacteria, this approach would serve to suppress the MIC below the clinically defined breakpoint for resistance and again render colistin therapy efficacious to treat infections for which otherwise there may be no effective antibiotics.
The emergence of resistance to multiple antimicrobial agents by pathogenic bacteria has become a significant global public health threat. Drug resistant bacterial infections cause considerable patient mortality and morbidity, and rising antibiotic resistance is seriously threatening the vast medical advancements made possible by antibiotics over the past 70 years. Therefore, multi-drug resistant bacterial infections present an enormous ongoing challenge and the development of novel approaches to treat these pathogens is considered an area of acute medical need.