Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition

Shyam, M and Verma, H and Bhattacharje, G and Mukherjee, P and Singh, S and Kamilya, S and Jalani, P and Das, S and Dasgupta, A and Mondal, A and Das, AK and Singh, A and Brucoli, F and Bagnéris, C and Dickman, R and Basavanakatti, VN and Naresh Babu, P and Sankaran, V and Dev, A and Sinha, BN and Bhakta, S and Jayaprakash, V (2022) Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition. In: Journal of Medicinal Chemistry, 65 (1). pp. 234-256.

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Abstract

In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds 44 and 49 as potential mycobactin biosynthesis inhibitors against mycobacteria. Moreover, candidates efficiently eradicated intracellularly surviving mycobacteria. Thermofluorimetric analysis and molecular dynamics simulations suggested that compounds 44 and 49 bind to salicyl-AMP ligase (MbtA), a key enzyme in the mycobactin biosynthetic pathway. To the best of our knowledge, these are the first rationally designed mycobactin inhibitors to demonstrate an excellent in vivo pharmacokinetic profile. In addition, these compounds also exhibited more potent whole-cell efflux pump inhibition than known efflux pump inhibitors verapamil and chlorpromazine. Results from this study pave the way for the development of 3-(2-hydroxyphenyl)-5-(aryl)-pyrazolines as a new weapon against superbug-associated AMR challenges. © 2022 American Chemical Society.

Item Type:	Journal Article
Publication:	Journal of Medicinal Chemistry
Publisher:	American Chemical Society
Additional Information:	The copyright for this article belongs to American Chemical Society
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology Division of Biological Sciences > Centre for Infectious Disease Research Division of Chemical Sciences > Solid State & Structural Chemistry Unit
Date Deposited:	01 Feb 2022 12:37
Last Modified:	19 Sep 2022 05:30
URI:	https://eprints.iisc.ac.in/id/eprint/71209

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