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 pn...

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Autores principales:	Michelle M. C. Buckner, M. Laura Ciusa, Richard W. Meek, Alice R. Moorey, Gregory E. McCallum, Emma L. Prentice, Jeremy P. Reid, Luke J. Alderwick, Alessandro Di Maio, Laura J. V. Piddock
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antimicrobial resistance E. coli K. pneumoniae ESBL carbapenemases KPC Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/877cafc750ec47c2b401c0945918e09f
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spelling	oai:doaj.org-article:877cafc750ec47c2b401c0945918e09f2021-11-15T15:56:57ZHIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes10.1128/mBio.03355-192150-7511https://doaj.org/article/877cafc750ec47c2b401c0945918e09f2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03355-19https://doaj.org/toc/2150-7511ABSTRACT 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.Michelle M. C. BucknerM. Laura CiusaRichard W. MeekAlice R. MooreyGregory E. McCallumEmma L. PrenticeJeremy P. ReidLuke J. AlderwickAlessandro Di MaioLaura J. V. PiddockAmerican Society for Microbiologyarticleantimicrobial resistanceE. coliK. pneumoniaeESBLcarbapenemasesKPCMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial resistance E. coli K. pneumoniae ESBL carbapenemases KPC Microbiology QR1-502
spellingShingle	antimicrobial resistance E. coli K. pneumoniae ESBL carbapenemases KPC Microbiology QR1-502 Michelle M. C. Buckner M. Laura Ciusa Richard W. Meek Alice R. Moorey Gregory E. McCallum Emma L. Prentice Jeremy P. Reid Luke J. Alderwick Alessandro Di Maio Laura J. V. Piddock HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
description	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.
format	article
author	Michelle M. C. Buckner M. Laura Ciusa Richard W. Meek Alice R. Moorey Gregory E. McCallum Emma L. Prentice Jeremy P. Reid Luke J. Alderwick Alessandro Di Maio Laura J. V. Piddock
author_facet	Michelle M. C. Buckner M. Laura Ciusa Richard W. Meek Alice R. Moorey Gregory E. McCallum Emma L. Prentice Jeremy P. Reid Luke J. Alderwick Alessandro Di Maio Laura J. V. Piddock
author_sort	Michelle M. C. Buckner
title	HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
title_short	HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
title_full	HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
title_fullStr	HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
title_full_unstemmed	HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes
title_sort	hiv drugs inhibit transfer of plasmids carrying extended-spectrum β-lactamase and carbapenemase genes
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/877cafc750ec47c2b401c0945918e09f
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HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

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