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, A.K. and Singh, A. and Brucoli, F. and Bagneris, Claire and Dickman, R. and Basavanakatti, V.N. and Naresh Babu, P. and Sankaran, V. and Dev, A. and Sinha, B.N. and Bhakta, Sanjib and Jayaprakash, V. (2022) Mycobactin analogues with excellent pharmacokinetic profile demonstrate potent antitubercular specific activity and exceptional efflux pump inhibition. Journal of Medicinal Chemistry 65 (1), pp. 234-256. ISSN 0022-2623.

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.

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