Zidovudine: A salvage therapy for  mcr-1  plasmid-mediated colistin-resistant bacterial infections?

Peyclit, Lucie; Baron, Sophie Alexandra; Yousfi, Hanane; Rolain, Jean‐Marc

doi:10.1016/j.ijantimicag.2018.03.012

Cited by 25 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, AZT-resistant E. coli and Salmonella were recovered from patients receiving AZT treatment for HIV infection (89,90). Recently, and in light of growing AMR, the antimicrobial properties of AZT have been explored (68)(69)(70)(71)73).…”

Section: Discussionmentioning

confidence: 99%

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

Buckner

Ciusa

Meek

et al. 2020

mBio

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Buckner

Ciusa

Meek

et al. 2020

mBio

View full text Add to dashboard Cite

show abstract

“…Zidovudine was activated in these bacteria by thymidine kinase (TK), and incorporation of activated zidovudine into bacterial DNA resulted in DNA chain termination (Figure 1; Elwell et al., 1987). Subsequently, zidovudine has been demonstrated to have potent activity against many pathogenic Gram-negative bacteria, including Escherichia coli , Salmonella typhimurium , Klebsiella pneumoniae , Shigella flexneri, and Haemophilus influenzae and including isolates resistant to conventional antibiotics (Keith et al., 1989; Sandrini et al., 2007a,b; Doleans-Jordheim et al., 2011; Peyclit et al., 2018). It also acts synergistically with conventional antibiotics, enhancing their effectiveness (Wambaugh et al., 2017; Ng et al., 2018; Falagas et al., 2019; Hu et al., 2019).…”

Section: Pyrimidine Analoguesmentioning

confidence: 99%

Nucleoside Analogues as Antibacterial Agents

2019

View full text Add to dashboard Cite

The rapid increase in antibiotic-resistant bacteria has emphasized the urgent need to identify new treatments for bacterial infections. One attractive approach, reducing the need for expensive and time-consuming clinical trials, is to repurpose existing clinically approved compounds for use as antibacterial agents. Nucleoside analogues are commonly used for treating viral and fungal infections, as well as for treating cancers, but have received relatively little attention as treatments for bacterial infections. However, a significant number of clinically approved derivatives of both pyrimidines and purines including halogenated, thiolated, and azolated compounds have been shown to have antibacterial activity. In the small number of studies carried out to date, such compounds have shown promise in treating bacterial infections. Here, we review the mechanisms of action and antibacterial activities of nucleoside analogues that can potentially be repurposed for treating infections as well as considering possible limitations in their usage.

show abstract

“…During the past decade, genome plasticity of human fungal pathogens has been strongly associated with their ability to acquire resistance to antifungals [9]. That is why many studies suggest to use other pharmacological classes and re-purposing old drugs either as a single antifungal agent or in combination with known antifungal drugs [10].…”

Section: Introductionmentioning

confidence: 99%

In vitro polymyxin activity against clinical multidrug-resistant fungi

Yousfi

Ranque

Rolain

et al. 2019

Antimicrob Resist Infect Control

Self Cite

View full text Add to dashboard Cite

Background Although antifungals are available and usually used against fungal infections, multidrug-resistant (MDR) fungal pathogens are a growing problem for public health. Moreover, fungal infections have become more prevalent nowadays due to the increasing number of people living with immunodeficiency. Thus, previously rarely-isolated and/or unidentified fungal species including MDR yeast and moulds have emerged around the world. Recent works indicate that polymyxin antibiotics (polymyxin B and colistin) have potential antifungal proprieties. Therefore, investigating the in vitro activity of these molecules against clinical multidrug-resistant yeast and moulds could be very useful. Methods In this study, a total of 11 MDR yeast and filamentous fungal strains commonly reported in clinical settings were tested against polymyxin antibiotics. These include strains belonging to the Candida , Cryptococcus and Rhodotorula yeast genera, along with others belonging to the Aspergillus , Fusarium , Scedosporium , Lichtheimia and Rhizopus mould genera. The fungicidal or fungistatic action of colistin against clinical yeast strains was determined by the time-kill study. Further, a checkerboard assay for its combination with antifungal agents, usually used in clinical practices (amphotericin B, itraconazole, voriconazole), was carried out against multi-drug resistant fungal strains. Results Polymyxin B and colistin exhibited an antifungal activity against all MDR fungal strains tested with MICs ranging from 16 to 128 μg/ml, except for the Aspergillus species. In addition, colistin has a fungicidal action against yeast species, with minimum fungicidal concentrations ranging from 2 to 4 times MICs. It induces damage to the MDR Candida albicans membrane. A synergistic activity of colistin-amphotericin B and colistin-itraconazole associations against Candida albicans and Lichtheimia corymbifera strains, respectively, and colistin-fluconazole association against Rhodotorula mucilaginosa, was demonstrated using a checkerboard microdilution assay. Conclusion colistin could be proposed, in clinical practice, in association with other antifungals, to treat life-threatening fungal infections caused by MDR yeasts or moulds.

show abstract

Zidovudine: A salvage therapy for mcr-1 plasmid-mediated colistin-resistant bacterial infections?

Cited by 25 publications

References 29 publications

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

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

Nucleoside Analogues as Antibacterial Agents

In vitro polymyxin activity against clinical multidrug-resistant fungi

Contact Info

Product

Resources

About