2. Academic Validation
  3. Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition

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

  • J Med Chem. 2022 Jan 13;65(1):234-256. doi: 10.1021/acs.jmedchem.1c01349.
Mousumi Shyam 1 2,  Harshita Verma 2,  Gourab Bhattacharje 3,  Piyali Mukherjee,  Samsher Singh,  Sujit Kamilya 4,  Pushpendu Jalani 5,  Swetarka Das 5,  Arunava Dasgupta 5,  Abhishake Mondal 4,  Amit Kumar Das 3,  Amit Singh,  Federico Brucoli 6,  Claire Bagnéris 2,  Rachael Dickman 7,  Vinay N Basavanakatti 8,  Patibandla Naresh Babu 8,  Vadivelan Sankaran 8,  Abhimanyu Dev 1,  Barij Nayan Sinha 1,  Sanjib Bhakta 2,  Venkatesan Jayaprakash 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India.
  • 2 Mycobacteria Research Laboratory, Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, U.K.
  • 3 Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
  • 4 Solid State and Structural Chemistry Unit, Indian Institute of Science, CV Raman Avenue, Bangalore 560012, India.
  • 5 Microbiology Division, CSIR-Central Drug Research Institute, Sector 10 Janakipuram Extension, Sitapur Road, Lucknow 226031, India.
  • 6 Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, U.K.
  • 7 Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University of London, London WC1N 1AX, U.K.
  • 8 Eurofins Advinus Limited, 21 & 22, Peenya Industrial area, Bengaluru 560058, India.
PMID: 34981940 DOI: 10.1021/acs.jmedchem.1c01349
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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