Yohei Doi, MD, PhD, has been awarded funding of $2,363,249 for a five-year renewal grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled “Colistin resistance in extensively drug-resistant Gram-negative pathogens”. This proposal was submitted in response to the competitive funding opportunity entitled NIH Research Project Grant (Parent R01) under funding opportunity number PA-19-056.
Extensive drug resistance (XDR) in Gram-negative bacteria is widely recognized as a top priority public health issue. Colistin is often the only viable treatment option for infections caused by such pathogens, but morbidity and mortality are substantial even with colistin treatment. Furthermore, clinical use of colistin has led to the emergence of colistin-resistant strains. Our previous investigations have deepened understanding of colistin resistance mechanisms and their implications in A. baumannii, but have also identified new knowledge gaps. These include wide ranges of resistance observed in the presence of lipid A modifications with colistin minimal inhibitory concentrations (MICs) ranging from 4 mg/L to >256 mg/L, difficulties with defining colistin MICs in some strains, and apparent disconnect between in vitro activity and suboptimal clinical outcome, especially among patients with pneumonia.
This project advances our understanding of colistin resistance across various XDR pathogens, fills a critical knowledge gap that lies between in vitro and in vivo resistance to colistin, and explores novel colistin adjuvants in abrogating lipid A modifications and colistin resistance. This comprehensive effort will be realized by close and ongoing multidisciplinary collaboration representing clinical microbiology, glycolipidomics, and synthetic chemistry.