Polyamine mediated alteration of antibiotic susceptibility in Gram-negative bacteria: a novel solution for antimicrobial resistance

Compounds present at infection sites can change how bacteria respond to antibiotics, but these effects can be missed because standard antibiotic susceptibility tests do not fully mimic infection conditions. This gap may explain why lab results sometimes fail to predict treatment success in clinics. One such group of compounds, called polyamines, are abundant at infection sites but underrepresented in antibiotic susceptibility tests. Some bacterial species become resistant to polymyxins-a last-resort class of antibiotics-when exposed to polyamines. However, these findings were based on a few standard lab isolates, potentially creating a generalization of polyamines' effects on polymyxin resistance. Hence, I tested ~200 clinical isolates of the World Health Organizations critical priority pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae. In addition to polyamine-induced polymyxin resistance, I identified clinical isolates where polyamines reverse polymyxin resistance and isolates where polyamines have no effect on polymyxin susceptibility. Thus, I hypothesize that polyamines modulate polymyxin susceptibility in P. aeruginosa and K. pneumoniae through specific genetic determinants that are not universally shared across all clinical isolates and identifying them will reveal new ways to combat polymyxin resistance. The objectives of this project are to explain how polyamines reduce polymyxin resistance, identify the genetic reasons for the contrasting outcomes from polyamine-polymyxin combinations, and discover polyamine-like drugs to combat polymyxin resistance. I will take an interdisciplinary approach, using genetic screens, molecular biology, and microbiology to achieve my objectives. This work is significant because it will contribute to clarifying how bacteria respond to antibiotics in infection-relevant conditions, a necessity for improving treatment selection and it aims to identify a novel treatment strategy to combat polymyxin resistance.