creators_name: Mahey, Nisha
creators_name: Tambat, Rushikesh
creators_name: Kalia, Ritu
creators_name: Ingavale, Rajnita
creators_name: Kodesia, Akriti
creators_name: Chandal, Nishtha
creators_name: Kapoor, Srajan
creators_name: Verma, Dipesh Kumar
creators_name: Thakur, Krishan Gopal
creators_name: Jachak, Sanjay
creators_name: Nandanwar, Hemraj
type: article
datestamp: 2024-06-25 04:00:23
lastmod: 2024-06-25 04:00:23
metadata_visibility: show
title: Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential
ispublished: pub
subjects: QR
note: OPEN ACCESS 
abstract: 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
date_type: published
publication: PLOS PATHOGENS
volume: 20
number: 4
id_number: 10.1371/journal.ppat.1012121
refereed: TRUE
official_url: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012121#abstract0
citation:   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).