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Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential
 
Creator Mahey, Nisha
Tambat, Rushikesh
Kalia, Ritu
Ingavale, Rajnita
Kodesia, Akriti
Chandal, Nishtha
Kapoor, Srajan
Verma, Dipesh Kumar
Thakur, Krishan Gopal
Jachak, Sanjay
Nandanwar, Hemraj
 
Subject QR Microbiology
 
Description Efflux pumps of the resistance-nodulation-cell division (RND) superfamily, particularly the AcrAB-TolC, and MexAB-OprM, besides mediating intrinsic and acquired resistance, also intervene in bacterial pathogenicity. Inhibitors of such pumps could restore the activities of antibiotics and curb bacterial virulence. Here, we identify pyrrole-based compounds that boost antibiotic activity in Escherichia coli and Pseudomonas aeruginosa by inhibiting their archetype RND transporters. Molecular docking and biophysical studies revealed that the EPIs bind to AcrB. The identified efflux pump inhibitors (EPIs) inhibit the efflux of fluorescent probes, attenuate persister formation, extend post-antibiotic effect, and diminish resistant mutant development. The bacterial membranes remained intact upon exposure to the EPIs. EPIs also possess an anti-pathogenic potential and attenuate P. aeruginosa virulence in vivo. The intracellular invasion of E. coli and P. aeruginosa inside the macrophages was hampered upon treatment with the lead EPI. The excellent efficacy of the EPI-antibiotic combination was evidenced in animal lung infection and sepsis protection models. These findings indicate that EPIs discovered herein with negligible toxicity are potential antibiotic adjuvants to address life-threatening Gram-negative bacterial infections.
 
Date 2024-04
 
Type Article
PeerReviewed
 
Relation https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012121#abstract0
http://crdd.osdd.net/open/3139/
 
Identifier Mahey, Nisha and Tambat, Rushikesh and Kalia, Ritu and Ingavale, Rajnita and Kodesia, Akriti and Chandal, Nishtha and Kapoor, Srajan and Verma, Dipesh Kumar and Thakur, Krishan Gopal and Jachak, Sanjay and Nandanwar, Hemraj (2024) Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential. PLOS PATHOGENS, 20 (4).