Abstract
Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB). Resistance to colistin severely restricts therapeutic options. To tackle this dire situation, urgent measures to restore colistin sensitivity are needed. In this study, whole-genome sequencing of colistin-resistant E. coli strain was performed and the genome analysis revealed that the strain belonged to the sequence type ST405. Multiple mutations were observed in genes implicated in colistin resistance, especially those related to the L-Ara-4-N pathway but mgrB was unmutated and mcr1-9 genes were missing. MarR inhibitor salicylate was used to re-sensitize this strain to colistin, which increased the negative charge on the cell surface especially in colistin resistant E. coli (U3790 strain) and thereby facilitated a decrease in colistin MIC by 8 fold. It is indeed well known that MarR inhibition by salicylate triggers the expression of AcrAB efflux pumps through MarA. So, in order to fully restore colistin sensitivity, a potent efflux pump inhibitor (BC1), identified earlier by this group was employed. The combination of colistin with both salicylate and BC1 caused a remarkable 6 log reduction in cell counts of U3790 in time-kill assay. Infection of muscle tissue of zebrafish with U3790 followed by various treatments showed that the combination of colistin + salicylate + BC1 was highly effective in reducing bioburden in infected muscle tissue by 4 log fold. Thus, our study shows that a combination of MarR inhibitor to enhance colistin binding and efflux pump inhibitor to reduce colistin extrusion was highly effective in restoring colistin sensitivity in colistin-resistant clinical isolate of E. coli in vitro and in vivo.
Highlights
Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB)
Rise in infections caused by multidrug-resistant (MDR) pathogens prompted WHO to declare a list of 12 priority Antimicrobial resistance (AMR) pathogens in 2017, of which, carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella spp, Serratia spp, Proteus spp) fall under critical priority group[1]
Because colistin interacts with bacterial cell surface depending on its electronic charge, we explored whether MarR inhibitor would partially restore colistin sensitivity in colistin resistant clinical isolate of E. coli
Summary
Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB). Our study shows that a combination of MarR inhibitor to enhance colistin binding and efflux pump inhibitor to reduce colistin extrusion was highly effective in restoring colistin sensitivity in colistin-resistant clinical isolate of E. coli in vitro and in vivo. Because colistin interacts with bacterial cell surface depending on its electronic charge, we explored whether MarR inhibitor (salicylate) would partially restore colistin sensitivity in colistin resistant clinical isolate of E. coli. Since MarR inhibition could be counterproductive by leading to enhanced antibiotic resistance predominantly through AcrAB-TolC pump, in the present work, we have evaluated combination of MarR inhibitor along with a non – toxic efflux pump inhibitor (benzochromenes) identified earlier by our group (against NorA pump of S. aureus)[16], to fully restore colistin sensitivity in colistin-resistant E. coli in vitro and in vivo
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