NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo
ABSTRACT The complexity and duration of tuberculosis (TB) treatment contributes to the emergence of drug resistant tuberculosis (DR-TB) and drug-associated side effects. Alternate chemotherapeutic agents are needed to shorten the time and improve efficacy of current treatment. In this study, we have...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.02592-22 |
| _version_ | 1798003820790284288 |
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| author | Padam Singh Srishti Rawat Ashish Kumar Agrahari Manisha Singh Saurabh Chugh Sudagar Gurcha Albel Singh Katherine Abrahams Gurdyal S. Besra Shailendra Asthana Diwan S. Rawat Ramandeep Singh |
| author_facet | Padam Singh Srishti Rawat Ashish Kumar Agrahari Manisha Singh Saurabh Chugh Sudagar Gurcha Albel Singh Katherine Abrahams Gurdyal S. Besra Shailendra Asthana Diwan S. Rawat Ramandeep Singh |
| author_sort | Padam Singh |
| collection | DOAJ |
| description | ABSTRACT The complexity and duration of tuberculosis (TB) treatment contributes to the emergence of drug resistant tuberculosis (DR-TB) and drug-associated side effects. Alternate chemotherapeutic agents are needed to shorten the time and improve efficacy of current treatment. In this study, we have assessed the antitubercular activity of NSC19723, a benzaldehyde thiosemicarbazone molecule. NSC19723 is structurally similar to thiacetazone (TAC), a second-line anti-TB drug used to treat individuals with DR-TB. NSC19723 displayed better MIC values than TAC against Mycobacterium tuberculosis and Mycobacterium bovis BCG. In our checkerboard experiments, NSC19723 displayed better profiles than TAC in combination with known first-line and recently approved drugs. Mechanistic studies revealed that NSC19723 inhibits mycolic acid biosynthesis by targeting the HadABC complex. Computational studies revealed that the binding pocket of HadAB is similarly occupied by NSC19723 and TAC. NSC19723 also improved the efficacy of isoniazid in macrophages and mouse models of infection. Cumulatively, we have identified a benzaldehyde thiosemicarbazone scaffold that improved the activity of TB drugs in liquid cultures, macrophages, and mice. IMPORTANCE Mycobacterium tuberculosis, the causative agent of TB is among the leading causes of death among infectious diseases in humans. This situation has worsened due to the failure of BCG vaccines and the increased number of cases with HIV-TB coinfections and drug-resistant strains. Another challenge in the field is the lengthy duration of therapy for drug-sensitive and -resistant TB. Here, we have deciphered the mechanism of action of NSC19723, benzaldehyde thiosemicarbazone. We show that NSC19723 targets HadABC complex and inhibits mycolic acid biosynthesis. We also show that NSC19723 enhances the activity of known drugs in liquid cultures, macrophages, and mice. We have also performed molecular docking studies to identify the interacting residues of HadAB with NSC19723. Taken together, we demonstrate that NSC19723, a benzaldehyde thiosemicarbazone, has better antitubercular activity than thiacetazone. |
| first_indexed | 2024-04-11T12:13:48Z |
| format | Article |
| id | doaj.art-4c455146b10e4a6782f523375f037d3a |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-11T12:13:48Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-4c455146b10e4a6782f523375f037d3a2022-12-22T04:24:25ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-12-0110610.1128/spectrum.02592-22NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In VivoPadam Singh0Srishti Rawat1Ashish Kumar Agrahari2Manisha Singh3Saurabh Chugh4Sudagar Gurcha5Albel Singh6Katherine Abrahams7Gurdyal S. Besra8Shailendra Asthana9Diwan S. Rawat10Ramandeep Singh11Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaDepartment of Chemistry, University of Delhi, Delhi, IndiaTranslational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaTranslational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaTranslational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaInstitute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United KingdomInstitute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United KingdomInstitute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United KingdomInstitute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, United KingdomTranslational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaDepartment of Chemistry, University of Delhi, Delhi, IndiaTranslational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, IndiaABSTRACT The complexity and duration of tuberculosis (TB) treatment contributes to the emergence of drug resistant tuberculosis (DR-TB) and drug-associated side effects. Alternate chemotherapeutic agents are needed to shorten the time and improve efficacy of current treatment. In this study, we have assessed the antitubercular activity of NSC19723, a benzaldehyde thiosemicarbazone molecule. NSC19723 is structurally similar to thiacetazone (TAC), a second-line anti-TB drug used to treat individuals with DR-TB. NSC19723 displayed better MIC values than TAC against Mycobacterium tuberculosis and Mycobacterium bovis BCG. In our checkerboard experiments, NSC19723 displayed better profiles than TAC in combination with known first-line and recently approved drugs. Mechanistic studies revealed that NSC19723 inhibits mycolic acid biosynthesis by targeting the HadABC complex. Computational studies revealed that the binding pocket of HadAB is similarly occupied by NSC19723 and TAC. NSC19723 also improved the efficacy of isoniazid in macrophages and mouse models of infection. Cumulatively, we have identified a benzaldehyde thiosemicarbazone scaffold that improved the activity of TB drugs in liquid cultures, macrophages, and mice. IMPORTANCE Mycobacterium tuberculosis, the causative agent of TB is among the leading causes of death among infectious diseases in humans. This situation has worsened due to the failure of BCG vaccines and the increased number of cases with HIV-TB coinfections and drug-resistant strains. Another challenge in the field is the lengthy duration of therapy for drug-sensitive and -resistant TB. Here, we have deciphered the mechanism of action of NSC19723, benzaldehyde thiosemicarbazone. We show that NSC19723 targets HadABC complex and inhibits mycolic acid biosynthesis. We also show that NSC19723 enhances the activity of known drugs in liquid cultures, macrophages, and mice. We have also performed molecular docking studies to identify the interacting residues of HadAB with NSC19723. Taken together, we demonstrate that NSC19723, a benzaldehyde thiosemicarbazone, has better antitubercular activity than thiacetazone.https://journals.asm.org/doi/10.1128/spectrum.02592-22Mycobacterium tuberculosisNSC19723HadABCsynergythiacetazone |
| spellingShingle | Padam Singh Srishti Rawat Ashish Kumar Agrahari Manisha Singh Saurabh Chugh Sudagar Gurcha Albel Singh Katherine Abrahams Gurdyal S. Besra Shailendra Asthana Diwan S. Rawat Ramandeep Singh NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo Microbiology Spectrum Mycobacterium tuberculosis NSC19723 HadABC synergy thiacetazone |
| title | NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo |
| title_full | NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo |
| title_fullStr | NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo |
| title_full_unstemmed | NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo |
| title_short | NSC19723, a Thiacetazone-Like Benzaldehyde Thiosemicarbazone Improves the Efficacy of TB Drugs In Vitro and In Vivo |
| title_sort | nsc19723 a thiacetazone like benzaldehyde thiosemicarbazone improves the efficacy of tb drugs in vitro and in vivo |
| topic | Mycobacterium tuberculosis NSC19723 HadABC synergy thiacetazone |
| url | https://journals.asm.org/doi/10.1128/spectrum.02592-22 |
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