TY  - JOUR
N1  - OPEN ACCESS 
ID  - open3139
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1012121#abstract0
IS  - 4
A1  - Mahey, Nisha
A1  - Tambat, Rushikesh
A1  - Kalia, Ritu
A1  - Ingavale, Rajnita
A1  - Kodesia, Akriti
A1  - Chandal, Nishtha
A1  - Kapoor, Srajan
A1  - Verma, Dipesh Kumar
A1  - Thakur, Krishan Gopal
A1  - Jachak, Sanjay
A1  - Nandanwar, Hemraj
Y1  - 2024/04//
N2  - 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.
JF  - PLOS PATHOGENS
VL  - 20
TI  - Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential
ER  -