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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/1404
Title: The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition
Authors: Bhattacharyya T.
Sharma A.
Akhter J.
Pathania, R.
Published in: International Journal of Antimicrobial Agents
Abstract: Efflux pumps are one of the major determinants of multiple drug resistance. In this study, AbeM, a multidrug efflux pump in Acinetobacter baumannii, was cloned into a multicopy plasmid (pUC18) and was transformed into an efflux-deficient mutant of Escherichia coli (KAM32). The elevated resistance profile of the recombinant E. coli for ciprofloxacin was utilised to screen a small-molecule library of 8000 molecules to identify IITR08027, a small molecule that is not inhibitory on its own but that could potentiate the activity of ciprofloxacin. When used in combination against A. baumannii, the molecule improves the killing efficiency of ciprofloxacin, extends its post-antibiotic effect and causes a decrease in frequency of resistant mutant selection with the antibiotic. Quinacrine-based fluorescence quenching and membrane depolarisation assays revealed that IITR08027 functions as a proton gradient inhibitor. This extends the activity of IITR08027 against other H+-driven efflux pumps such as AbeS. MTT assay against HeLa and HEK293 cells suggested that the molecule is non-toxic at its minimum effective concentration. We propose that, in combination with fluoroquinolones (ciprofloxacin and norfloxacin), IITR08027 may be effective against multidrug-resistant A. baumannii expressing AbeM or other efflux pumps that use the proton gradient as an efflux mechanism. © 2017 Elsevier B.V. and International Society of Chemotherapy
Citation: International Journal of Antimicrobial Agents (2017), 50(2): 219-226
URI: https://doi.org/10.1016/j.ijantimicag.2017.03.005
http://repository.iitr.ac.in/handle/123456789/1404
Issue Date: 2017
Publisher: Elsevier B.V.
Keywords: Antibiotic resistance
Clinical strains
Combination therapy
Transporters
ISSN: 9248579
Author Scopus IDs: 56763662400
57217481823
57201851128
7004308029
Author Affiliations: Bhattacharyya, T., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Sharma, A., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Akhter, J., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Pathania, R., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India
Funding Details: Funding: This work was supported by the Indian Council of Medical Research (ICMR) (New Delhi, India) [research grant no. AMR/15/2011-ECD-I], awarded to RP. TB and JA are thankful to the ICMR for financial support. AS is financially supported by the Ministry of Human Resource Development, Government of India.
Corresponding Author: Pathania, R.; Department of Biotechnology, Indian Institute of Technology RoorkeeIndia; email: ranjanapathania@gmail.com
Appears in Collections:Journal Publications [BT]

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