Restoring #colistin sensitivity in colistin-resistant #Ecoli: Combinatorial use of MarR inhibitor with efflux pump inhibitor (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2019 Dec 25;9(1):19845. doi: 10.1038/s41598-019-56325-x.

Restoring colistin sensitivity in colistin-resistant E. coli: Combinatorial use of MarR inhibitor with efflux pump inhibitor.

Sundaramoorthy NS1, Suresh P2, Selva Ganesan S2, GaneshPrasad A1, Nagarajan S3.

Author information: 1 Center for Research on Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. 2 Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. 3 Center for Research on Infectious Diseases, School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, Tamil Nadu, India. sai@scbt.sastra.edu.

 

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.

PMID: 31882661 DOI: 10.1038/s41598-019-56325-x

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Colistin; Enterobacteriaceae.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.