Menaquinone analogs inhibit growth of bacterial pathogens.

Abstract

Gram-positive bacteria cause serious human illnesses through combinations of cell surface and secreted virulence factors. We initiated studies with four of these organisms to develop novel topical antibacterial agents that interfere with growth and exotoxin production, focusing on menaquinone analogs. Menadione, 1,4-naphthoquinone, and coenzymes Q1 to Q3 but not menaquinone, phylloquinone, or coenzyme Q10 inhibited the growth and to a greater extent exotoxin production of Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, and Streptococcus agalactiae at concentrations of 10 to 200 μg/ml. Coenzyme Q1 reduced the ability of S. aureus to cause toxic shock syndrome in a rabbit model, inhibited the growth of four Gram-negative bacteria, and synergized with another antimicrobial agent, glycerol monolaurate, to inhibit S. aureus growth. The staphylococcal two-component system SrrA/B was shown to be an antibacterial target of coenzyme Q1. We hypothesize that menaquinone analogs both induce toxic reactive oxygen species and affect bacterial plasma membranes and biosynthetic machinery to interfere with two-component systems, respiration, and macromolecular synthesis. These compounds represent a novel class of potential topical therapeutic agents.

• Authors: Patrick M Schlievert, Joseph A Merriman, Wilmara Salgado-Pabón, Elizabeth A Mueller, Adam R Spaulding, Bao G Vu, Olivia N Chuang-Smith, Petra L Kohler, John R Kirby
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 11 Pg. 5432-7 (Nov 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23959313 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Exotoxins
• Laurates
• Monoglycerides
• Reactive Oxygen Species
• Repressor Proteins
• SrrA protein, Staphyolococcus aureus
• SrrB protein, Staphyolococcus aureus
• Vitamin K 2
• monolaurin

Topics

• Administration, Topical
• Animals
• Anti-Bacterial Agents (pharmacology)
• Bacillus anthracis (drug effects, growth & development)
• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Cell Membrane (drug effects)
• Drug Synergism
• Exotoxins (antagonists & inhibitors, metabolism)
• Humans
• Laurates (pharmacology)
• Monoglycerides (pharmacology)
• Rabbits
• Reactive Oxygen Species (metabolism)
• Repressor Proteins (antagonists & inhibitors, metabolism)
• Shock, Septic (drug therapy, microbiology)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects, growth & development, metabolism)
• Streptococcus agalactiae (drug effects, growth & development)
• Streptococcus pyogenes (drug effects, growth & development)
• Vitamin K 2 (pharmacology)