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      Mutation EthA W21R confers co-resistance to prothionamide and ethionamide in both Mycobacterium bovis BCG and Mycobacterium tuberculosis H37Rv

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          Abstract

          Ethionamide (ETA) and prothionamide (PRO) are interchangeably used in tuberculosis (TB) chemotherapy regimens. Subtle discrepancies between biochemical and genetic information on the modes of sensitivity and resistance of isoniazid (INH) and ETA warrants further studies. We report a new mutation – EthA W21R – in Mycobacterium bovis Bacillus Calmette-Guérin that corresponds with co-resistance to both PRO and ETA, which to the best of our knowledge has not been reported before. Our findings suggest that mutation EthA W21R could be used as a marker site for testing PRO and ETA cross-resistance.

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          inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis.

          A. Banerjee, E Dubnau, A Quémard … (1994)
          Isoniazid (isonicotinic acid hydrazide, INH) is one of the most widely used antituberculosis drugs, yet its precise target of action on Mycobacterium tuberculosis is unknown. A missense mutation within the mycobacterial inhA gene was shown to confer resistance to both INH and ethionamide (ETH) in M. smegmatis and in M. bovis. The wild-type inhA gene also conferred INH and ETH resistance when transferred on a multicopy plasmid vector to M. smegmatis and M. bovis BCG. The InhA protein shows significant sequence conservation with the Escherichia coli enzyme EnvM, and cell-free assays indicate that it may be involved in mycolic acid biosynthesis. These results suggest that InhA is likely a primary target of action for INH and ETH.
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            Mechanism of thioamide drug action against tuberculosis and leprosy

            Feng Wang, ROBERT LANGLEY, Gulcin Gulten … (2007)
            Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target–drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.
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              Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis.

              Simon Barry, M. Bosman, K Mdluli … (2000)
              Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of Mycobacterium tuberculosis (MTb) have allowed us to demonstrate that ETA is activated by S-oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG. We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity. Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [(14)C]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarlide.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Infect Drug Resist
                Journal ID (iso-abbrev): Infect Drug Resist
                Journal ID (publisher-id): Infection and Drug Resistance
                Title: Infection and Drug Resistance
                Publisher: Dove Medical Press
                ISSN (Electronic): 1178-6973
                Publication date Collection: 2018
                Publication date (Electronic): 13 June 2018
                Volume: 11
                Pages: 891-894
                Affiliations
                [1 ]State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), Guangzhou, China
                [2 ]University of Chinese Academy of Sciences, Beijing, China
                [3 ]Department of Biological Sciences, University of Embu, Embu, Kenya
                [4 ]State Key Laboratory of Respiratory Disease, Department of Clinical Laboratory, Guangzhou Chest Hospital, Guangzhou
                [5 ]Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
                Author notes
                Correspondence: Shouyong Tan, State Key Laboratory of Respiratory Diseases, Department of Clinical Laboratory, Guangzhou Chest Hospital, No. 62, Hengzhigang Road, Yuexiu District, Guangzhou, China, Tel +86 20 8348 8601, Email tanshouyong@ 123456163.com
                Tianyu Zhang, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences (CAS), No. 190 Kaiyuan Ave, Room A132, Science Park, New Huangpu District, Guangzhou, Guangdong 510530, China, Tel +86 32 015 270, Email zhang_tianyu@ 123456gibh.ac.cn
                [*]

                These authors contributed equally to this work

                Article
                Publisher ID: idr-11-891
                DOI: 10.2147/IDR.S163965
                PMC ID: 6005328
                SO-VID: 7807c283-92c7-41e2-9481-46fb4ad30ee7
                Copyright © © 2018 Mugweru et al. This work is published and licensed by Dove Medical Press Limited
                License:

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Categories
                Subject: Short Report

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: mutation,ethaw21r,isoniazid,co-resistance,thioamides,molecular marker
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: mutation, ethaw21r, isoniazid, co-resistance, thioamides, molecular marker

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