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A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa
 
Creator Tambat, Rushikesh
Mahey, Nisha
Chandal, Nishtha
Verma, Dipesh Kumar
Jangra, Manoj
Thakur, Gopal Krishan
Nandanwar, Hemraj
 
Subject QR Microbiology
 
Description The use of efflux pump inhibitors (EPIs) as potentiators along with the traditional antibiotics assists in the warfare against antibiotic-resistant superbugs. Efflux pumps of the resistance-nodulation-cell division (RND) family play crucial roles in multidrug resistance in Escherichia coli and Pseudomonas aeruginosa. Despite several efforts, clinically useful inhibitors are not available at present. This study describes ethyl 4-bromopyrrole-2-carboxylate (RP1) isolation, an inhibitor of RND transporters from the library of 4000 microbial exudates. RP1 acts synergistically with antibiotics by reducing their minimum inhibitory concentration in strains overexpressing archetype RND transporters (AcrAB-TolC and MexAB-OprM). It also improves the accumulation of Hoechst 33342 and inhibits its efflux (a hallmark of EPI functionality). The antibiotic-RP1 combinations prolong the postantibiotic effects and reduce the mutation prevention concentration of antibiotics. Additionally, from Biolayer Interferometry spectra, it appears that RP1 is bound to AcrB. RP1 displays low mammalian cytotoxicity, no Ca2+ channel inhibitory effects, and reduces the intracellular invasion of E. coli and P. aeruginosa in macrophages. Furthermore, the RP1-levofloxacin combination is nontoxic, well-tolerated, and notably effective in a murine lung infection model. In sum, RP1 is a potent EPI and worthy of further consideration as a potentiator to improve the effectiveness of existing antibiotics.
 
Publisher ACS Publications
 
Date 2022-01-19
 
Type Article
PeerReviewed
 
Relation https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00281
http://crdd.osdd.net/open/2996/
 
Identifier Tambat, Rushikesh and Mahey, Nisha and Chandal, Nishtha and Verma, Dipesh Kumar and Jangra, Manoj and Thakur, Gopal Krishan and Nandanwar, Hemraj (2022) A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa. ACS Infectious Diseases , 8 (2). pp. 255-270.