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Detection of a target protein (GroEl2) in Mycobacterium tuberculosis using a derivative of 1,2,4-triazolethiols

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Abstract

Herein, we identified a potent lead compound RRA2, within a series of 54 derivatives of 1,2,4-triazolethiols (exhibit good potency as an anti-mycobacterial agents) against intracellular Mycobacterium tuberculosis (Mtb). Compound RRA2 showed significant mycobactericidal activity against active stage Mycobacterium bovis BCG and Mtb with minimum inhibitory concentration (MIC) values of 2.3 and 2.0 µg/mL, respectively. At MIC value, RRA2 compound yielded 0.82 log reduction of colony-forming unit (cfu) against non-replicating Mtb. Furthermore, RRA2 compound was selected for further target identification due to the presence of alkyne group, showing higher selectivity index (> 66.66 ± 0.22, in non-replicating stage). Using “click” chemistry, we synthesized the biotin linker-RRA2 conjugate, purified with HPLC method and confirmed the conjugation of biotin linker-RRA2 complex by HR-MS analysis. Furthermore, we successfully pulled down and identified a specific target protein GroEl2, from Mtb whole-cell extract. Furthermore, computational molecular modeling indicated RRA2 could interact with GroEl2, which explains the structure–activity relationship observed in this study.

Graphical abstract

GroEL-2 identified a potent and specific target protein for RRA 2 compound in whole cell extract of Mtb H37Ra.

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Acknowledgements

We are thankful to AstraZeneca, Bangalore, MTCC Chandigarh, India, and Dr. Shekhar Mande, NCCS, Pune (DG CSIR), for providing M. bovis BCG (ATCC 35745), M. smegmatis (ATCC 607) and, M. tuberculosis H37Ra (ATCC 25177) and purified GroEl1 and GroEl2 from M.tuberculosis H37Rv, respectively. Thanks to the Rebecca L Cooper Medical Research Foundation and Director, National Chemical Laboratory, Pune, India, for providing financial support.

Funding

Sarvesh K Soni is the recipient of research grants from Rebecca L Cooper Medical Research Foundation (PG2018098) and ATSE- Priming grant PG181. Sagar Swami has been awarded Senior Research Fellowship (SRF) File no: 31/011(0983)2017/EMR-01) from the Council of Scientific & Industrial Research (CSIR) New Delhi, India.

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  1. Sampa Sarkar and Sagar Swami have contributed equally.

Authors and Affiliations

  1. School of Science, STEM College, Engineering and Health, RMIT University, GPO Box 2476, Melbourne, VIC, 3001, Australia

    Sampa Sarkar, Sarvesh Kumar Soni & Jessica K. Holien

  2. Combi-Chem Bio-Resource Centre, Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune, Maharashtra, 411 008, India

    Sampa Sarkar, Sagar Swami, Arshad Khan & Dhiman Sarkar

  3. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, India

    Sagar Swami & Dhiman Sarkar

  4. Institute of Academic Medicine and Weill Cornell Medical College, Houston, Houston, TX, 77030, USA

    Arshad Khan

  5. Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, Maharashtra, 411 008, India

    Arvind M. Korwar

  6. Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune, Maharashtra, 411 008, India

    Anjali P. Likhite, Ramesh A. Joshi & Rohini R. Joshi

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  1. Sampa Sarkar
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Contributions

Dhiman Sarkar has conceived the experiments and provided an interpretation of the results. Sampa Sarkar, Sagar Swami, Arshad Khan, Sarvesh Soni and Jessica Holien performed the experiments and analysed the data. Sarvesh Soni and Jessica Holien assisted with analysis and interpretation. Dhiman Sarkar, Sampa Sarkar, Sarvesh Soni and Sagar Swami wrote the final manuscript draft.

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Correspondence to Dhiman Sarkar.

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Sarkar, S., Swami, S., Soni, S.K. et al. Detection of a target protein (GroEl2) in Mycobacterium tuberculosis using a derivative of 1,2,4-triazolethiols. Mol Divers 26, 2535–2548 (2022). https://doi.org/10.1007/s11030-021-10351-y

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