A Broad-Spectrum Horizontal Transfer Inhibitor Prevents Transmission of Plasmids Carrying Multiple Antibiotic Resistance Genes

Abstract

The dissemination of antimicrobial resistance (AMR) severely degrades the performance of antibiotics and constantly paralyzes the global health system. In particular, plasmid-mediated transfer of antibiotic resistance genes (ARGs) across bacteria is recognized as the primary driver. Therefore, antiplasmid transfer approaches are urgently warranted to resolve this intractable problem. Herein, we demonstrated the potential of azidothymidine (AZT), an FDA-approved anti-HIV drug, as a broad-spectrum horizontal transfer inhibitor to effectively prevent the transmission of multiple ARGs, including mcr-1, blaNDM−5, and tet(X4), both in vitro and in vivo. It was also noteworthy that the inhibitory effect of AZT was proved to be valid within and across bacterial genera under different mating conditions. Mechanistic studies revealed that AZT dissipated bacterial proton motive force, which was indispensable for ATP synthesis and flagellar motility. In addition, AZT downregulated bacterial secretion systems involving general and type IV secretion systems (T4SS). Furthermore, the thymidine kinase, which is associated with DNA synthesis, turned out to be the potential target of AZT. Collectively, our work demonstrates the broad inhibitory effect of AZT in preventing ARGs transmission, opening new horizons for controlling AMR.