Mitoxantrone synergies with tigecycline against Klebsiella pneumoniae.

The global health threat of antimicrobial resistance necessitates the development of novel therapeutic strategies. This study identifies the anticancer agent mitoxantrone as a potent antimicrobial against Klebsiella pneumoniae. Through passaging experiments, we demonstrate that resistance to mitoxantrone arises via mutations in the kstR2 gene, leading to the overexpression of the SmvA efflux pump. Transcriptomic analysis reveals that mitoxantrone treatment induces the bacterial SOS response, likely due to DNA damage. Critically, we found that mitoxantrone exhibits a synergistic effect with tigecycline against K. pneumoniae, both in vitro and in a murine wound infection model. Mechanistically, this synergy is driven by tigecycline-mediated enhancement of intracellular mitoxantrone accumulation. These findings reveal a potentially effective combination regimen to combat K. pneumoniae infections.IMPORTANCEThe rise of antibiotic-resistant Klebsiella pneumoniae demands new treatment options. This study uncovers that mitoxantrone, a drug currently approved for cancer therapy, is effective against K. pneumoniae. Furthermore, we discovered that combining mitoxantrone with the existing antibiotic tigecycline is synergistic against K. pneumoniae. We found that tigecycline enhances mitoxantrone accumulation inside bacterial cells. Overall, our work identified the tigecycline-mitoxantrone combination as a promising strategy to treat K. pneumoniae infections.