Abstract
Bacterial infections remain a leading killer worldwide, which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae are prevalent and extremely difficult to treat. Repurposing existing drugs and improving the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here, we investigated the in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae, including strains producing extended-spectrum beta-lactamases (ESBLs) or New Delhi metallo-beta-lactamase 1 (NDM) or carrying mobilized colistin resistance (mcr-1). The MIC was determined using the broth microdilution method. The combined effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. The fractional inhibitory concentration index from the checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae strains, respectively, 100% of NDM-1-producing strains, and 92% of mcr-1-producing E. coli strains. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In a murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. The AZT and colistin combination possesses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.