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Open AccessArticle

A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles

1
Fondazione Policlinico Universitario A. Gemelli, IRCCS Rome. Largo A. Gemelli 8, 00168 Rome, Italy
2
Department of Biotechnology (DoE 2018-2022), Chemistry and Pharmacy (DoE 2018-2022), University of Siena, via Aldo Moro 2, 53100 Siena, Italy
3
Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy
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Institute of Microbiology, Università Cattolica del Sacro Cuore, Roma–Largo F. Vito 1, 00168 Rome, Italy
5
Mater Olbia Hospital, SS 125 Orientale Sarda, 07026 Olbia, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Daniele Castagnolo
Molecules 2019, 24(23), 4373; https://doi.org/10.3390/molecules24234373
Received: 5 November 2019 / Revised: 23 November 2019 / Accepted: 25 November 2019 / Published: 29 November 2019
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles. View Full-Text
Keywords: multi-targeting drugs; tuberculosis; computational methods; FDA-approved drugs; drug repurposing multi-targeting drugs; tuberculosis; computational methods; FDA-approved drugs; drug repurposing
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Battah, B.; Chemi, G.; Butini, S.; Campiani, G.; Brogi, S.; Delogu, G.; Gemma, S. A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles. Molecules 2019, 24, 4373.

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