Repurposing antiviral drugs as a new avenue for Klebsiella pneumoniae decolonization

Abstract

Klebsiella pneumoniae (Kp) is an antibiotic-resistant pathogen that colonizes the gastrointestinal tract and can disseminate to peripheral sites, causing infections including bacteremia, urinary tract infections, and pneumonia. Intestinal Kp colonization is a risk factor for subsequent infection, as colonizing strains frequently correspond to infecting isolates. Thus, targeting Kp at the site of colonization through decolonization strategies may mitigate infection risk. Here, we evaluated repurposing existing drugs not indicated for antibacterial use as candidates for Kp decolonization. We screened an antiviral compound library for activity against Kp and identified and validated six compounds with poorly characterized anti-Kp activity. Screening a library of clinical Kp strains against a subset of these compounds revealed strain-specific activity that varied by compound. We further tested these compounds under conditions relevant to the human gut and found that their activity depended on biological context. Focusing on 3'-azido-3'-deoxythymidine (zidovudine or AZT), the most successful candidate in the human ex vivo experiments, a transposon mutant screen identified multiple genetic determinants of AZT susceptibility, including genes involved in DNA maintenance and central metabolism. Serial passage of Kp in AZT resulted in the repeated emergence of mutations in tdk, which encodes thymidine kinase, suggesting that alterations in thymidine metabolism contribute to AZT resistance. Finally, we show that development of AZT resistance leads to collateral sensitivity to trimethoprim, suggesting potential for combination treatment and providing insight into mechanisms governing AZT susceptibility and resistance in Kp. Collectively, these findings support further investigation of antiviral drugs as potential gut decolonization therapies for Kp.