Bacteria exposed to antiviral drugs develop antibiotic cross-resistance and unique resistance profiles

Abstract

Antiviral drugs are used globally as treatment and prophylaxis for long-term and acute viral infections. Even though antivirals also have been shown to have off-target effects on bacterial growth, the potential contributions of antivirals to antimicrobial resistance remains unknown. Herein we explored the ability of different classes of antiviral drugs to induce antimicrobial resistance. Our results establish the previously unrecognized capacity of antivirals to broadly alter the phenotypic antimicrobial resistance profiles of both gram-negative and gram-positive bacteria Escherichia coli and Bacillus cereus. Bacteria exposed to antivirals including zidovudine, dolutegravir and raltegravir developed cross-resistance to commonly used antibiotics including trimethoprim, tetracycline, clarithromycin, erythromycin, and amoxicillin. Whole genome sequencing of antiviral-resistant E. coli isolates revealed numerous unique single base pair mutations, as well as multi-base pair insertions and deletions, in genes with known and suspected roles in antimicrobial resistance including those coding for multidrug efflux pumps, carbohydrate transport, and cellular metabolism. The observed phenotypic changes coupled with genotypic results indicate that bacteria exposed to antiviral drugs with antibacterial properties in vitro can develop multiple resistance mutations that confer cross-resistance to antibiotics. Our findings underscore the potential contribution of wide scale usage of antiviral drugs to the development and spread of antimicrobial resistance in humans and the environment.

In vitro antibacterial activity of antiretroviral drugs on key commensal bacteria from the human microbiota

“…To our knowledge this is the first study to report BIC and EVG antibacterial activity. A previous study by Wallace et al (Wallace et al, 2023) reported that DTG and Raltegravir (RAL) significantly reduced E. coli and B. cereus growth at concentrations ≥ 50 µg/mL. However, in our study we did not observe DTG and RAL antibacterial activity against tested E. coli strains.…”

“…This study has limitations. As previously mentioned, there are differences between the antiretroviral antibacterial activity obtained in this study compared to the data presented by previous research ( Ray et al., 2021 ; Wallace et al., 2023 ) probably due to the strains used; most of which being clinical isolates or different reference strains that might behave differently in the presence of the drug compared to the set of strains tested in our study. Additionally, MIC determination was tested using only one methodology and it could have been confirmed by other complementary techniques such as biomass evaluation by optical density, colony forming unit counting or DEAD/LIVE assays.…”

“…Further studies are needed to elucidate EVG mechanism of action against Gram-positive bacteria and to investigate the pharmacological parameters that ensure the therapeutic efficiency versus the side effects associated with this ARV. In this context, the discovery of ARVs with antibacterial spectrum also raises important issues regarding the impact of ARV against the development of multidrug resistant microorganisms as well as regarding its ecotoxicological impact against the environment ( Ncube et al., 2018 ; Wallace et al., 2023 ).…”

“…and E. faecalis clinical strains which was not confirmed in our study using the reference strains. Additionally, Shilaih et al (Shilaih et al, 2018) has previously identified EFV activity against Bacillus subtilis and Wallace et al (Wallace et al, 2023) identified EFV activity against B. cereus and E. coli. Of note, EFV activity against E. coli was not observed in our study and previous research (Shilaih et al, 2018;Ray et al, 2021).…”

Non-Canonical Aspects of Antibiotics and Antibiotic Resistance

“…Chloroxylenol promotes conjugation [133]. OTHER DRUGS Antivirals (zidovudine, dolutegravir, raltegravir) select for cross-resistance vs. trimethoprim, amoxicillin, tetracycline, and macrolides [134] Carbamazepine promotes conjugation at environmentally relevant concentrations [135]. It is worth noting that carbamazepine is the most frequently detected drug in rivers worldwide [136].…”