Premium
Menaquinone Biosynthesis: An Antibacterial Target?
Author(s) -
Matarlo Joe
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.612.2
Subject(s) - pharmacophore , mycobacterium tuberculosis , antimicrobial , chemistry , staphylococcus aureus , microbiology and biotechnology , drug , drug discovery , biochemistry , antibiotics , drug development , enzyme , bacteria , tuberculosis , pharmacology , biology , medicine , genetics , pathology
The rise in drug‐resistant “superbugs” necessitates the need for novel antimicrobial agents and/or novel drug targets. Lipoquinones, such as menaquinone (MK), are biologically active electron transporters that play pivotal roles in all living organisms. MK is the sole electron carrier in the electron transport chain of many deadly human pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis , making the MK biosynthesis pathway an attractive target for new antimicrobial drug development. MenE is an essential enzyme which catalyzes a concerted ligation of CoA to o ‐succinylbenzoate (OSB) via an ordered enzymatic mechanism in the presence of a divalent cation and ATP. In this work, we combined biochemistry, molecular biology, microbiology, structural biology, and medicinal chemistry to design, develop, and probe the active pharmacophore of our lead inhibitor, OSB‐AMS and showed that it is a potent inhibitor of MenE in M. tuberculosis and MRSA. Furthermore, we discovered a novel inhibitor scaffold to target MenE and showed that it has potent anti‐tubercular activity. Metabolomics analysis showed that MK levels in treated MRSA drastically decreased at sub‐MIC levels and addition of exogenous MK rescues these bacteria, proving on‐target inhibition. Overall, our work shows promising drug discovery results and inhibitors described herein can be further developed to potentially treat drug‐resistant superbugs. Support or Funding Information NIH ‐ R01 GM102864Crystal structure of MenE in complex with OSB‐AMS.