HIV Drugs Inhibit Transfer of Plasmids Carrying Extended- Spectrum Beta-Lactamase and Carbapenemase Genes
Michelle M. C. Buckner A, M. Laura Ciusa ARWM, Gregory E. McCallum AELP, Alessandro Di Maio C, Piddock LJV
mBio - vol. 11 1-18 (2020)
Antimicrobial-resistant (AMR) infections pose a serious risk to human and animal health. A major factor contributing to this global crisis is the sharing of resistance genes between different bacteria via plasmids. The WHO lists Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, producing extended-spectrum ␤-lactamases (ESBL) and carbapenemases as “critical” priorities for new drug development. These re- sistance genes are most often shared via plasmid transfer. However, finding methods to prevent resistance gene sharing has been hampered by the lack of screening systems for medium-/high-throughput approaches. Here, we have used an ESBL-producing plas- mid, pCT, and a carbapenemase-producing plasmid, pKpQIL, in two different Gram- negative bacteria, E. coli and K. pneumoniae. Using these critical resistance-pathogen combinations, we developed an assay using fluorescent proteins, flow cytometry, and confocal microscopy to assess plasmid transmission inhibition within bacterial popula- tions in a medium-throughput manner. Three compounds with some reports of antiplas- mid properties were tested; chlorpromazine reduced transmission of both plasmids and linoleic acid reduced transmission of pCT. We screened the Prestwick library of over 1,200 FDA-approved drugs/compounds. From this, we found two nucleoside analogue drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduced plasmid transmission (AZT, e.g., at 0.25?g/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plas- mid transmission was reduced by concentrations of the drugs which are below peak se- rum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids.