title: Discovery of bicyclic inhibitors against menaquinone biosynthesis.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Seoung-ryoung
authors.initials: SR
authors.lastname: Choi
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Marilynn A
authors.initials: MA
authors.lastname: Larson
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Hinrichs
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Bartling
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Frandsen
authors.affiliation: Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA.
authors.forename: Prabagaran
authors.initials: P
authors.lastname: Narayanasamy
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D024482:Vitamin K 2 / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D024482:Vitamin K 2; C573554:1,4-dihydroxy-2-naphthoate prenyltransferase, Mycobacterium tuberculosis; D019883:Alkyl and Aryl Transferases