Microbe-Derived Indole Metabolite Demonstrates Potent Multidrug Efflux Pump Inhibition in .

Tambat, Rushikesh and Jangra, Manoj and Mahey, Nisha and Chandal, Nishtha and Kaur, Manpreet and Chaudhary, Surbhi and Verma, Dipesh Kumar and Thakur, Krishan Gopal and Raje, Manoj and Jachak, Sanjay and Khatri, Neeraj and Nandanwar, Hemraj (2019) Microbe-Derived Indole Metabolite Demonstrates Potent Multidrug Efflux Pump Inhibition in . Frontiers in microbiology, 10. p. 2153. ISSN 1664-302X

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Official URL: https://www.frontiersin.org/articles/10.3389/fmicb...


Efflux pumps are always at the forefront of bacterial multidrug resistance and account for the failure of antibiotics. The present study explored the potential of 2-(2-Aminophenyl) indole (RP2), an efflux pump inhibitor (EPI) isolated from the soil bacterium, to overcome the efflux-mediated resistance in . The RP2/antibiotic combination was tested against efflux pump over-expressed strains. The compound was further examined for the ethidium bromide (EtBr) uptake and efflux inhibition assay (a hallmark of EPI functionality) and cytoplasmic membrane depolarization. The safety profile of RP2 was investigated using cytotoxicity assay and Ca channel inhibitory effect. The efficacy of RP2 was studied in an animal model in combination with ciprofloxacin. RP2 exhibited the synergistic activity with several antibiotics in efflux pump over-expressed strains of . In the mechanistic experiments, RP2 increased the accumulation of EtBr, and demonstrated the inhibition of its efflux. The antibiotic-EPI combinations resulted in extended post antibiotic effects as well as a decrease in mutation prevention concentration of antibiotics. Additionally, the docking studies suggested the binding of RP2 to the active site of modeled structure of NorA efflux pump. The compound displayed low mammalian cytotoxicity and had no Ca channel inhibitory effect. In experiments, RP2 reduced the intracellular invasion of in macrophages. Furthermore, the RP2/ciprofloxacin combination demonstrated remarkable efficacy in a murine thigh infection model. In conclusion, RP2 represents a promising candidate as bacterial EPI, which can be used in the form of a novel therapeutic regimen along with existing and upcoming antibiotics, for the eradication of infections.

Item Type: Article
Additional Information: Copyright of this article belongs to Frontiers
Uncontrolled Keywords: combination therapy; efflux pump inhibitor; membrane potential; multidrug resistance; natural products; post-antibiotic effect; time-kill kinetics
Subjects: Q Science > QR Microbiology
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 05 Dec 2019 14:36
Last Modified: 05 Dec 2019 14:36
URI: http://crdd.osdd.net/open/id/eprint/2482

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