Journal Article

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

Kodesia, Akriti, Verma, Dipesh Kumar, Mahey, Nisha, Kalia, Ritu, Ingavale, Rajnita, Chandal, Nishtha, Nandanwar, Hemraj, Thakur, Krishan Gopal, Kapoor, Srajan, Tambat, Rushikesh, Jachak, Sanjay

2024

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adjuvants / Analysis / Antibacterial agents / Antibiotic resistance / Antibiotics / Antimicrobial agents / Bacteria / Bacterial diseases / Bacterial infections / Biocompatibility / Biology and Life Sciences / Bronchopulmonary infection / Care and treatment / Cell division / Complications and side effects / Dosage and administration / Drug resistance / Drug resistance in microorganisms / E coli / Efflux / Escherichia coli / Fluorescent indicators / Gram-negative bacteria / Gram-negative bacterial infections / Health aspects / Inhibitors / Macrophages / Medicine and Health Sciences / Molecular docking / Nodulation / Pathogenicity / Pathogens / Prevention / Pseudomonas aeruginosa / Pumps / Research and Analysis Methods / Resistant mutant / Sepsis / Tetracycline / Tetracyclines / Toxicity / Virulence / Virulence (Microbiology)