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Optimization of a Benzothiazole Indolene Scaffold Targeting Bacterial Cell Wall Assembly

Authors Chauhan J, Yu W, Cardinale S, Opperman TJ, MacKerell AD Jr, Fletcher S, de Leeuw EPH

Received 7 August 2019

Accepted for publication 30 December 2019

Published 10 February 2020 Volume 2020:14 Pages 567—574


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Qiongyu Guo

Jay Chauhan,1 Wenbo Yu,2 Steven Cardinale,3 Timothy J Opperman,3 Alexander D MacKerell Jr,2,4 Steven Fletcher,1 Erik PH de Leeuw1

1Institute of Human Virology & Department of Biochemistry and Molecular Biology of the University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA; 2Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, MD 21201, USA; 3Microbiotix, LLC., Worcester, MA 01605, USA; 4Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD 21201, USA

Correspondence: Erik PH de Leeuw
Tel +1 410 706 3430

Background: The bacterial cell envelope is comprised of the cell membrane and the cell wall. The bacterial cell wall provides rigidity to the cell and protects the organism from potential harmful substances also. Cell wall biosynthesis is an important physiological process for bacterial survival and thus has been a primary target for the development of antibacterials. Antimicrobial peptides that target bacterial cell wall assembly are abundant and many bind to the essential cell wall precursor molecule Lipid II.
Methods: We describe the structure-to-activity (SAR) relationship of an antimicrobial peptide-derived small molecule 7771– 0701 that acts as a novel agent against cell wall biosynthesis. Derivatives of compound 7771– 0701 (2-[(1E)-3-[(2E)-5,6-dimethyl-3-(prop-2-en-1-yl)-1,3-benzothiazol-2-ylidene]prop-1-en-1-yl]-1,3,3-trimethylindol-1-ium) were generated by medicinal chemistry guided by Computer-Aided Drug Design and NMR. Derivatives were tested for antibacterial activity and Lipid II binding.
Results: Our results show that the N-alkyl moiety is subject to change without affecting functionality and further show the functional importance of the sulfur in the scaffold. The greatest potency against Gram-positive bacteria and Lipid II affinity was achieved by incorporation of a bromide at the R3 position of the benzothiazole ring.
Conclusion: We identify optimized small molecule benzothiazole indolene scaffolds that bind to Lipid II for further development as antibacterial therapeutics.

Keywords: Lipid II, antibiotics, drug development, cell wall

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