creators_name: Tambat, Rushikesh
creators_name: Jangra, Manoj
creators_name: Mahey, Nisha
creators_name: Chandal, Nishtha
creators_name: Kaur, Manpreet
creators_name: Chaudhary, Surbhi
creators_name: Verma, Dipesh Kumar
creators_name: Thakur, Krishan Gopal
creators_name: Raje, Manoj
creators_name: Jachak, Sanjay
creators_name: Khatri, Neeraj
creators_name: Nandanwar, Hemraj
type: article
datestamp: 2019-12-05 14:36:13
lastmod: 2019-12-05 14:36:13
metadata_visibility: show
title: Microbe-Derived Indole Metabolite Demonstrates Potent Multidrug Efflux Pump Inhibition in .
ispublished: pub
subjects: QR
keywords: combination therapy; efflux pump inhibitor; membrane potential; multidrug resistance; natural products; post-antibiotic effect; time-kill kinetics


note: Copyright of this article belongs to Frontiers 
abstract: 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.
date: 2019
date_type: published
publication: Frontiers in microbiology
volume: 10
publisher: Frontiers
pagerange: 2153
refereed: TRUE
issn: 1664-302X
official_url: https://www.frontiersin.org/articles/10.3389/fmicb.2019.02153/full
citation:   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