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      Towards a new combination therapy for tuberculosis with next generation benzothiazinones

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          Abstract

          The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.

          Subject Categories Microbiology, Virology & Host Pathogen Interaction; Pharmacology & Drug Discovery

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          Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism.

          Kristin N. Adams, Kevin Takaki, Lynn E. Connolly … (2011)
          Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug or more specific efflux pump inhibitors to standard antitubercular therapy should shorten the duration of curative treatment. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis.

            Timothy P Stinear, Torsten Seemann, Paul F. Harrison … (2008)
            Mycobacterium marinum, a ubiquitous pathogen of fish and amphibia, is a near relative of Mycobacterium tuberculosis, the etiologic agent of tuberculosis in humans. The genome of the M strain of M. marinum comprises a 6,636,827-bp circular chromosome with 5424 CDS, 10 prophages, and a 23-kb mercury-resistance plasmid. Prominent features are the very large number of genes (57) encoding polyketide synthases (PKSs) and nonribosomal peptide synthases (NRPSs) and the most extensive repertoire yet reported of the mycobacteria-restricted PE and PPE proteins, and related-ESX secretion systems. Some of the NRPS genes comprise a novel family and seem to have been acquired horizontally. M. marinum is used widely as a model organism to study M. tuberculosis pathogenesis, and genome comparisons confirmed the close genetic relationship between these two species, as they share 3000 orthologs with an average amino acid identity of 85%. Comparisons with the more distantly related Mycobacterium avium subspecies paratuberculosis and Mycobacterium smegmatis reveal how an ancestral generalist mycobacterium evolved into M. tuberculosis and M. marinum. M. tuberculosis has undergone genome downsizing and extensive lateral gene transfer to become a specialized pathogen of humans and other primates without retaining an environmental niche. M. marinum has maintained a large genome so as to retain the capacity for environmental survival while becoming a broad host range pathogen that produces disease strikingly similar to M. tuberculosis. The work described herein provides a foundation for using M. marinum to better understand the determinants of pathogenesis of tuberculosis.
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              Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

              Sheshagiri Gaonkar, Vadim Makarov, V. Balasubramanian … (2009)
              New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (publisher-id): emmm
                Title: EMBO Molecular Medicine
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Print): March 2014
                Publication date (Electronic): 05 February 2014
                Volume: 6
                Issue: 3
                Pages: 372-383
                Affiliations
                [1 ]More Medicines for Tuberculosis (MM4TB) Consortium http://www.mm4tb.org
                [2 ]Bakh Institute of Biochemistry, Russian Academy of Science Moscow, Russia
                [3 ]Global Health Institute, Ecole Polytechnique Fédérale de Lausanne Lausanne, Switzerland
                [4 ]Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne Lausanne, Switzerland
                [5 ]Department Medical Microbiology and Infection Control, VU University Medical Center Amsterdam, The Netherlands
                [6 ]Division of Clinical Pharmacology, CHUV, Hôpital Beaumont Lausanne, Switzerland
                [7 ]Department of Molecular Microbiology, VU University Amsterdam, The Netherlands
                [8 ]Janssen Infectious Diseases Beerse, Belgium
                Author notes
                *Corresponding author. Tel: +41 21 693 1851; Fax: +41 21 693 1790; E-mail: stewart.cole@ 123456epfl.ch
                [‡]

                These authors contributed equally to this work.

                [†]

                Present address: ZF-screens BV, Leiden, The Netherlands

                Article
                DOI: 10.1002/emmm.201303575
                PMC ID: 3958311
                PubMed ID: 24500695
                SO-VID: 675e0e54-7721-4a82-921b-b11a8a33ff80
                Copyright © © 2014 The Authors.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 October 2013
                Date revision received : 04 December 2013
                Date accepted : 10 December 2013
                Categories
                Subject: Research Articles

                ScienceOpen disciplines: Molecular medicine
                Keywords: benzothiazinones,combination regimens,dpre1,tuberculosis
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: benzothiazinones, combination regimens, dpre1, tuberculosis

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