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Disulfiram Inhibits M. tuberculosis Growth by Altering Methionine Pool, Redox Status and Host-Immune Response

131 Pages Posted: 28 Oct 2020

See all articles by Deepika Chaudhary

Deepika Chaudhary

Government of India - Translational Health Science & Technology Institute (THSTI)

Mardiana Marzuki

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Andrea Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Rania Bouzeyen

Government of India - Translational Health Science & Technology Institute (THSTI)

Avantika Singh

Institute of Microbial Technology (CSIR) - Structural Biology Laboratory

Tannu Priya Gosain

Government of India - Translational Health Science & Technology Institute (THSTI)

Saqib Kidwai

Government of India - Translational Health Science & Technology Institute (THSTI)

Courtney Grady

Rutgers University - New Jersey Medical School, Division of Infectious Disease

Kholiswa Tsotetsi

Rutgers University - New Jersey Medical School, Division of Infectious Disease

Kiran Chawla

Manipal Academy of Higher Education (MAHE)

Shihui Foo

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Josephine Lum

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Sonu Kumar Gupta

Government of India - Translational Health Science & Technology Institute (THSTI)

Nisheeth Agarwal

Government of India - Translational Health Science & Technology Institute (THSTI)

Liana Tsenova

City University of New York (CUNY) - New York City College of Technology, Department of Biological Sciences

Yashwant Kumar

Government of India - Translational Health Science & Technology Institute (THSTI)

Bernett Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

Pradeep Kumar

Rutgers University - New Jersey Medical School, Division of Infectious Disease

Krishan Gopal Thakur

Institute of Microbial Technology (CSIR) - Structural Biology Laboratory

Ramandeep Singh

Government of India - Translational Health Science & Technology Institute (THSTI)

Amit Singhal

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

More...

Abstract

Methionine biosynthetic pathway, essential for the growth of Mycobacterium tuberculosis (Mtb) in the host, represents an attractive target for the development of novel anti-tuberculars. Here, we have biochemically characterized homoserine acetyl transferase (HSAT viz. MetA) of Mtb, which catalyses the first committed step of methionine and S-adenosylmethionine (SAM) biosynthesis. High-throughput screening of a 2300 compound library resulted in identification of thiram, an anti-fungal organosulfur compound, as the most potent MetA inhibitor. Further analysis of thiram analogs led to the identification of orally bioavailable disulfiram (DIS, an anti-alcoholism FDA approved drug) as a novel inhibitor of MetA. Both thiram and DIS restricted the growth of drug-sensitive and drug-resistant Mtb strains in a bactericidal manner. ThermoFlour assay demonstrated direct binding of DIS with MetA. Metabolomic and transcriptomic studies showed DIS mediated perturbation of methionine and redox homeostasis, respectively, in Mtb. In concordance, the effect of DIS on Mtb growth was partially rescued by supplementation with either L-methionine as well as N-acetyl cysteine, suggesting a multi-target killing mechanism. In Mtb-infected mice, DIS administration restricted bacterial growth, increased efficacy of isoniazid, ameliorated lung pathology,  modulated lung immune cell landscape and protective immune response. Taken together, our results demonstrate that DIS can be repurposed for designing an effective anti-tubercular therapy.

Funding Statement: The research fellowship to D.C. and T.P.G. from Department of Biotechnology, Govt. of India is acknowledged. Ava.S. fellowship was supported by the University of Grants commission. R.B. acknowledges Department of Science and Technology India and FICCI for providing C.V. Raman International fellowship. R.S. acknowledge THSTI, and Department of Biotechnology, Govt. of India (BT/PR29075/BRB/10/1699/2018) for funding. This research was supported by SIgN A*STAR, A*STAR JCO-CDA grant (#1518251030), and Singapore-India Joint grant (#1518224018) to A.S.

Declaration of Interests: None.

Ethics Approval Statement: The proposed animal experiments were approved by the institutional animal ethics committee of Defence Science Organization (DSO), Singapore.

Keywords: M. tuberculosis, Disulfiram, methionine pools, redox status, TB therapy.

Suggested Citation

Chaudhary, Deepika and Marzuki, Mardiana and Lee, Andrea and Bouzeyen, Rania and Singh, Avantika and Gosain, Tannu Priya and Kidwai, Saqib and Grady, Courtney and Tsotetsi, Kholiswa and Chawla, Kiran and Foo, Shihui and Lum, Josephine and Gupta, Sonu Kumar and Agarwal, Nisheeth and Tsenova, Liana and Kumar, Yashwant and Lee, Bernett and Kumar, Pradeep and Thakur, Krishan Gopal and Singh, Ramandeep and Singhal, Amit, Disulfiram Inhibits M. tuberculosis Growth by Altering Methionine Pool, Redox Status and Host-Immune Response. Available at SSRN: https://ssrn.com/abstract=3696891 or http://dx.doi.org/10.2139/ssrn.3696891

Deepika Chaudhary (Contact Author)

Government of India - Translational Health Science & Technology Institute (THSTI)

Faridabad, Haryana
India

Mardiana Marzuki

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN) ( email )

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Andrea Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Rania Bouzeyen

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Avantika Singh

Institute of Microbial Technology (CSIR) - Structural Biology Laboratory

Sec39-A
Chandigarh, 160036
India

Tannu Priya Gosain

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Saqib Kidwai

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Courtney Grady

Rutgers University - New Jersey Medical School, Division of Infectious Disease ( email )

NJ
United States

Kholiswa Tsotetsi

Rutgers University - New Jersey Medical School, Division of Infectious Disease ( email )

NJ
United States

Kiran Chawla

Manipal Academy of Higher Education (MAHE) ( email )

Madhav Nagar
Udupi
Manipal, IA Karnataka 576104
India

Shihui Foo

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN) ( email )

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Josephine Lum

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN)

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Sonu Kumar Gupta

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Nisheeth Agarwal

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Liana Tsenova

City University of New York (CUNY) - New York City College of Technology, Department of Biological Sciences ( email )

300 Jay Street - NAMM 914
Brooklyn, NY 11201
United States

Yashwant Kumar

Government of India - Translational Health Science & Technology Institute (THSTI)

Faridabad, Haryana
India

Bernett Lee

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN) ( email )

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

Pradeep Kumar

Rutgers University - New Jersey Medical School, Division of Infectious Disease

NJ
United States

Krishan Gopal Thakur

Institute of Microbial Technology (CSIR) - Structural Biology Laboratory ( email )

Sector 39 A
Chandigarh, 160036
India

Ramandeep Singh

Government of India - Translational Health Science & Technology Institute (THSTI) ( email )

Faridabad, Haryana
India

Amit Singhal

Agency for Science, Technology and Research (A*STAR) - Singapore Immunology Network (SIgN) ( email )

1 Fusionopolis Way
#16-16 Connexis
Singapore, 138632
Singapore

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