title: Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential
creator: Mahey, Nisha
creator: Tambat, Rushikesh
creator: Kalia, Ritu
creator: Ingavale, Rajnita
creator: Kodesia, Akriti
creator: Chandal, Nishtha
creator: Kapoor, Srajan
creator: Verma, Dipesh Kumar
creator: Thakur, Krishan Gopal
creator: Jachak, Sanjay
creator: 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
type: PeerReviewed
relation: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012121#abstract0
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).       
relation: http://crdd.osdd.net/open/3139/