Discovery of bicyclic inhibitors against menaquinone biosynthesis

Author:

Choi Seoung-ryoung1,Larson Marilynn A1,Hinrichs Steven H1,Bartling Amanda M1,Frandsen Joel1,Narayanasamy Prabagaran1

Affiliation:

1. Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198–5900, USA

Abstract

Introduction: Menaquinone is used for transporting electrons and is essential for the aerobic and anaerobic respiratory systems of all pathogens and prokaryotes. Many Gram-positive bacteria use only menaquinone in the electron transport system. Thus, menaquinone biosynthesis is a potential target for the development of inhibitors against bacteria including drug-resistant pathogens. Results: After modeling, synthesis and in vitro testing, we determined that 7-methoxy-2-naphthol-based inhibitors targeted the MenA enzyme of the menaquinone biosynthesis pathway. The developmental compounds 1 and 2 were active against Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus with a minimal inhibitory concentration of 3–5 μg/ml. Conclusion: Nontraditional bicyclic inhibitors, compounds 1 and 2 could serve as lead compounds for the development of an antimicrobial agent, with activities against M. tuberculosis and methicillin-resistant S. aureus.

Publisher

Future Science Ltd

Subject

Drug Discovery,Pharmacology,Molecular Medicine

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