Polyamine mediated alteration of antibiotic responses: a novel strategy for adjuvant treatment

Antimicrobial resistance (AMR), a phenomenon often referred to as the "silent pandemic" has been projected by the United Nations to cause over 10 million deaths world wide, a number that would surpass COVID or any other respiratory virus driven pandemic. Additionally, the AMR crisis is exacerbated by viral pandemics as seen during the COVID-19 pandemic. Thus, we are in dire need of new strategies to combat AMR. I have previously characterized altered macrolide antibiotic responses in K. pneumoniae when in the presence of polyamines, a small signaling compound present at the infection site secreted by both the host and microbe. These results led to the identification and characterization of a novel polyamine-analog drug that exhibits µM sensitivity in multidrug-resistant K. pneumoniae and enhances macrolide treatment when used in combination. Additionally, I have previously shown that the treatment of E. coli with quinolone antibiotics elicits increased production of polyamines which combat antibiotic treatment. In this work I will: (1) confirm the efficacy of the novel compound in in vivo models and confirm its mode of action, (2) define the signaling cascade that responds to quinolone treatment and the subsequent increased polyamine production to elucidate novel drug targets. I will employ an interdisciplinary approach that includes genomic screens, biochemical enzymatic assays, microbiology and molecular biology experiments and testing in an animal model. This work is significant as it may produce new treatment options for multidrug resistant bacteria and may uncover novel targets for combination therapies.