TY  - JOUR
N1  - The copyright of this article belongs to ACS Publications 
ID  - open2996
UR  - https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00281
IS  - 2
A1  - Tambat, Rushikesh
A1  - Mahey, Nisha
A1  - Chandal, Nishtha
A1  - Verma, Dipesh Kumar
A1  - Jangra, Manoj
A1  - Thakur, Gopal Krishan
A1  - Nandanwar, Hemraj
Y1  - 2022/01/19/
N2  - The use of efflux pump inhibitors (EPIs) as potentiators along with the traditional antibiotics assists in the warfare against antibiotic-resistant superbugs. Efflux pumps of the resistance-nodulation-cell division (RND) family play crucial roles in multidrug resistance in Escherichia coli and Pseudomonas aeruginosa. Despite several efforts, clinically useful inhibitors are not available at present. This study describes ethyl 4-bromopyrrole-2-carboxylate (RP1) isolation, an inhibitor of RND transporters from the library of 4000 microbial exudates. RP1 acts synergistically with antibiotics by reducing their minimum inhibitory concentration in strains overexpressing archetype RND transporters (AcrAB-TolC and MexAB-OprM). It also improves the accumulation of Hoechst 33342 and inhibits its efflux (a hallmark of EPI functionality). The antibiotic-RP1 combinations prolong the postantibiotic effects and reduce the mutation prevention concentration of antibiotics. Additionally, from Biolayer Interferometry spectra, it appears that RP1 is bound to AcrB. RP1 displays low mammalian cytotoxicity, no Ca2+ channel inhibitory effects, and reduces the intracellular invasion of E. coli and P. aeruginosa in macrophages. Furthermore, the RP1-levofloxacin combination is nontoxic, well-tolerated, and notably effective in a murine lung infection model. In sum, RP1 is a potent EPI and worthy of further consideration as a potentiator to improve the effectiveness of existing antibiotics.
PB  - ACS Publications 
JF  - ACS Infectious Diseases 
VL  - 8
KW  - ESKAPE pathogens; multidrug resistance (MDR); efflux pump inhibitor (EPI)' resistance-nodulation-cell division (RND); efflux pumps
TI  - A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa
SP  - 255
EP  - 270
ER  -