TY - JOUR
T1 - Detection of a target protein (GroEl2) in Mycobacterium tuberculosis using a derivative of 1,2,4-triazolethiols
AU - Sarkar, Sampa
AU - Swami, Sagar
AU - Soni, Sarvesh Kumar
AU - Holien, Jessica K.
AU - Khan, Arshad
AU - Korwar, Arvind M.
AU - Likhite, Anjali P.
AU - Joshi, Ramesh A.
AU - Joshi, Rohini R.
AU - Sarkar, Dhiman
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2022/10
Y1 - 2022/10
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
KW - 1,2,4-triazolethiols
KW - GroEl2
KW - Mycobactericidal activity
KW - Mycobacterium bovis BCG
KW - Mycobacterium tuberculosis
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U2 - 10.1007/s11030-021-10351-y
DO - 10.1007/s11030-021-10351-y
M3 - Article
AN - SCOPUS:85119854429
SN - 1381-1991
VL - 26
SP - 2535
EP - 2548
JO - Molecular Diversity
JF - Molecular Diversity
IS - 5
ER -