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

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• Antimicrobial resistance (AMR) poses a severe global health threat, driven primarily by the plasmid-mediated transfer of antibiotic resistance genes (ARGs).
• Developing strategies to inhibit the horizontal transfer of ARGs is crucial for combating AMR.

Purpose of the Study:

• To investigate the potential of azidothymidine (AZT), an FDA-approved anti-HIV drug, as a broad-spectrum inhibitor of ARG horizontal transfer.
• To evaluate the efficacy of AZT in preventing the transmission of key ARGs, including mcr-1, blaNDM-5, and tet(X4).

Main Methods:

• In vitro and in vivo experiments were conducted to assess AZT's inhibitory effects on ARG transfer.
• Mechanistic studies were performed to elucidate the mode of action of AZT, including its impact on bacterial energetics, motility, secretion systems, and potential molecular targets.

Main Results:

• AZT demonstrated broad-spectrum efficacy in inhibiting the horizontal transfer of multiple ARGs (mcr-1, blaNDM-5, tet(X4)) across and within bacterial genera.
• AZT was found to dissipate the bacterial proton motive force, affecting ATP synthesis and flagellar motility.
• AZT downregulated general and type IV secretion systems (T4SS) and potentially targets thymidine kinase involved in DNA synthesis.

Conclusions:

• Azidothymidine (AZT) shows significant potential as a novel therapeutic agent to control the spread of antimicrobial resistance.
• AZT's broad-spectrum activity and multifaceted mechanism of action offer a promising new strategy for combating the global health challenge of AMR.