HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

Abstract

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 β-lactamases (ESBL) and carbapenemases as “critical” priorities for new drug development. These resistance 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 plasmid, 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 populations in a medium-throughput manner. Three compounds with some reports of antiplasmid 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 μg/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plasmid transmission was reduced by concentrations of the drugs which are below peak serum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids. IMPORTANCE More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-based system to search for drugs that will stop bacteria from sharing resistance genes. We uncovered a new role for two drugs used to treat HIV and show that they are able to prevent the sharing of two different types of resistance genes in two unique bacterial strains. This work lays the foundation for future work to reduce the prevalence of resistant infections.

Evolutionary Pathways and Trajectories in Antibiotic Resistance

“…A number of antimicrobials have been suggested as having plasmid-curing activity, such as novobiocin, rifampicin, 4-quinolone derivatives (1225,1226), agents with weak antibacterial activity such as ascorbic acid (1227), and thiazine heterocyclic compounds, such as phenothiazines, which act on cell membranes and are clinically employed in psychiatric and allergic diseases (1228). Anti-HIV drugs such as abacavir and azidothymidine have also been shown to reduce interbacterial plasmid transfer (1229,1230).…”

Combining Functional Genomics and Whole-Genome Sequencing to Detect Antibiotic Resistance Genes in Bacterial Strains Co-Occurring Simultaneously in a Brazilian Hospital

“…Therefore, the rapid evolution of plasmids through structural rearrangements, acquisition of virulence genes, plasmid fusions, and propagation to pathogens can account for the fast dissemination of super-virulent or super-resistant bacteria [ 21 , 22 , 23 ]. Understanding the very dynamic and complex processes could hold the potential for the design of new drugs aiming at reducing plasmid propagation between pathogens [ 24 ]. While the use of WGS is currently growing worldwide, most studies (especially in Brazil) have been restricted to some particular species (such as K. pneumoniae or S. aureus ), without considering the importance of other species as repositories of antibiotic resistance genes (ARGs) in hospital settings.…”

Linoleic acid and α‐linolenic acid inhibit conjugative transfer of an IncX4 plasmid carryingmcr‐1

“…Contrary to this view, another literature showed that LA at 3 mmol l −1 effectively inhibit conjugation of the plasmid pCT, which encodes an ATPase TrbB originated from plasmid RP4 (Inc P) (Buckner et al . 2020). This difference is likely to be due to different compounds and concentrations in two literature.…”