Abstract
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.
Highlights
Tuberculosis (TB), a disease caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is one of the top 10 causes of death worldwide, accounting for 1.7 million deaths and 10.0 million new cases in 2017 [1]
We previously discovered inhibitors of the zinc-dependent metalloprotease-1 (Zmp1), a virulence factor essential for Mycobacterium tuberculosis (Mtb) survival inside macrophages, which were proven to be able to impair the survival of Mtb inside macrophages with no activity on axenic
We identified a second enzyme, peptide deformylase (PDF), that was chosen for our virtual screening campaign based on its role in Mtb growth and its possible active-site similarities with Zmp1 [17,18]
Summary
Tuberculosis (TB), a disease caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is one of the top 10 causes of death worldwide, accounting for 1.7 million deaths and 10.0 million new cases in 2017 [1]. Chemotherapy of TB is still a challenging task due to several factors related both to the specific biology of Mtb and the need to prevent the emergence of drug resistance. These factors translate to long-lasting and complex treatment approaches [2]. The combination of a multi-target affinity profile in a single NME is a challenging but widely accepted strategy to overcome rapid development of resistance and to increase the therapeutic lifespan of drugs in both anti-infective and anticancer chemotherapies [9,10,11]
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