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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/1113
Title: Antibacterial properties and in vivo efficacy of a novel nitrofuran, IITR06144, against MDR pathogens
Authors: Bhando T.
Bhattacharyya T.
Gaurav A.
Akhter J.
Saini M.
Gupta V.K.
Srivastava S.K.
Sen H.
Navani, Naveen Kumar
Gupta V.
Biswas D.
Chaudhry R.
Pathania, R.
Published in: Journal of Antimicrobial Chemotherapy
Abstract: Objectives: The emergence of MDR Gram-negative pathogens and increasing prevalence of chronic infections presents an unmet need for the discovery of novel antibacterial agents. The aim of this study was to evaluate the biological properties of a small molecule, IITR06144, identified in a phenotypic screen against the Gram-negative model organism Escherichia coli. Methods: A small-molecule library of 10956 compounds was screened for growth inhibition against E. coli ATCC 25922 at concentration 50 ?M. MICs of lead compounds were determined by the broth microdilution method. Time-kill kinetics, anti-persister activity, spontaneous frequency of resistance, biofilm inhibition and disruption were assessed by standard protocols. Resistant mutants were generated by serial passaging followed by WGS. In vitro toxicity studies were carried out via the MTT assay. In vivo toxicity and efficacy in a mouse model were also evaluated. Results: IITR06144 was identified as the most promising candidate amongst 29 other potential antibacterial leads, exhibiting the lowest MIC, 0.5 mg/L. IITR06144 belongs to the nitrofuran class and exhibited broad-spectrum bactericidal activity against most MDR bacteria, including the 'priority pathogen', carbapenem-resistant Acinetobacter baumannii. IITR06144 retained its potency against nitrofurantoin-resistant clinical isolates. It displayed anti-persister, anti-biofilm activity and lack of spontaneous resistance development. IITR06144 demonstrated a large therapeutic index with no associated in vitro and in vivo toxicity. Conclusions: In the light of excellent in vitro properties displayed by IITR06144 coupled with its considerable in vivo efficacy, further evaluation of IITR06144 as a therapeutic lead against antibiotic-resistant infections is warranted. © 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Citation: Journal of Antimicrobial Chemotherapy (2020), 75(2): 418-428
URI: https://doi.org/10.1093/jac/dkz428
http://repository.iitr.ac.in/handle/123456789/1113
Issue Date: 2020
Publisher: Oxford University Press
ISSN: 3057453
Author Scopus IDs: 56266736600
56763662400
57205694539
57201851128
57204465219
57196262614
57202143131
57214237121
6507073924
36610005500
36815262200
7005816135
7004308029
Author Affiliations: Bhando, T., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Bhattacharyya, T., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India, Department of Biology, University of North Dakota, Grand Forks, ND 58202-9019, United States
Gaurav, A., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Akhter, J., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Saini, M., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Gupta, V.K., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India, Department of Biochemistry and Molecular Biology, Hebrew University of Jerusalem, Jerusalem, 91904, Israel
Srivastava, S.K., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India, SynCTI, Centre of Life Sciences, National University of Singapore, Singapore, 117456, Singapore
Sen, H., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Navani, N.K., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Gupta, V., Department of Microbiology, Government Medical College and Hospital, Chandigarh, India
Biswas, D., Department of Microbiology, All India Institute of Medical Sciences, Bhopal, India
Chaudhry, R., Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India
Pathania, R., Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, 247667, India
Funding Details: This study was supported by Department of Science and Technology-Science and Engineering Research Board (DST-SERB) by the Indian Government under the grant no. EMR/2016/007116 (SER-1246-DMC) to R.P. Support was also provided by DST-SERB and Ministry of Human Resource Development (MHRD) to T.B. in the form of Junior Research Fellowship (JRF) and Senior Research Fellowship (SRF). The funding agencies were not involved in the conduct of the study, the preparation of the manuscript or the decision to submit the manuscript for publication.
Corresponding Author: Pathania, R.; Department of Biotechnology, Indian Institute of Technology RoorkeeIndia; email: rpathfbs@iitr.ac.in
Appears in Collections:Journal Publications [BT]

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