title: Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm.
abstract: Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 μg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1β. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.
authors.affiliation: Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Seoung-Ryoung
authors.initials: SR
authors.lastname: Choi
authors.affiliation: Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Frandsen
authors.affiliation: Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Prabagaran
authors.initials: P
authors.lastname: Narayanasamy
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001420:Bacteria, Aerobic / Q000187:drug effects / Q000254:growth & development; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development*; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D000074084:THP-1 Cells; D024482:Vitamin K 2 / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D024482:Vitamin K 2; D019883:Alkyl and Aryl Transferases