Journal: |
Microbiology Spectrum
American Society for Microbiology
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Abstract: |
Control and management of life-threatening bacterial and fungal infections
are a global health challenge. Despite advances in antimicrobial therapies,
treatment failures for resistant bacterial and fungal infections continue to increase.
We aimed to repurpose the anthelmintic drug rafoxanide for use with existing therapeutic
drugs to increase the possibility of better managing infection and decrease
treatment failures. For this purpose, we evaluated the antibacterial and antifungal
potential of rafoxanide. Notably, 70% (70/100) of bacterial isolates showed multidrug
resistance (MDR) patterns, with higher prevalence among human isolates (73.5% [50/68])
than animal ones (62.5% [20/32]). Moreover, 22 fungal isolates (88%) were MDR and
were more prevalent among animal (88.9%) than human (87.5%) sources. We observed
alarming MDR patterns among bacterial isolates, i.e., Klebsiella pneumoniae (75% [30/40; 8
animal and 22 human]) and Escherichia coli (66% [40/60; 12 animal and 28 human]), and
fungal isolates, i.e., Candida albicans (86.7% [13/15; 4 animal and 9 human]) and
Aspergillus fumigatus (90% [9/10; 4 animal and 5 human]), that were resistant to at least
one agent in three or more different antimicrobial classes. Rafoxanide had antibacterial
and antifungal activities, with minimal inhibitory concentration (MICs) ranging from 2 to
128 mg/mL. Rafoxanide at sub-MICs downregulated the mRNA expression of resistance
genes, including E. coli and K. pneumoniae blaCTX-M-1, blaTEM-1, blaSHV, MOX, and DHA, C.
albicans ERG11, and A. fumigatus cyp51A. We noted the improvement in the activity of
b-lactam and antifungal drugs upon combination with rafoxanide. This was apparent in
the reduction in the MICs of cefotaxime and fluconazole when these drugs were combined
with sub-MIC levels of rafoxanide. There was obvious synergism between rafoxanide
and cefotaxime against all E. coli and K. pneumoniae isolates (fractional inhibitory
concentration index [FICI] values # 0.5). Accordingly, there was a shift in the patterns of
resistance of 16.7% of E. coli and 22.5% of K. pneumoniae isolates to cefotaxime and those
of 63.2% of C. albicans and A. fumigatus isolates to fluconazole when the isolates were
treated with sub-MICs of rafoxanide. These results were confirmed by in silico and mouse protection assays. Based on the in silico study, one possible explanation for how rafoxanide
reduced bacterial resistance is through its inhibitory effects on bacterial and fungal histidine
kinase enzymes. In short, rafoxanide exhibited promising results in overcoming bacterial
and fungal drug resistance.
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