Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases

• Published in: Biochimica et biophysica acta 2009-02, Vol.1787 (2), p.129-133
• Main Authors: Mogi, Tatsushi, Ui, Hideaki, Shiomi, Kazuro, Ōmura, Satoshi, Miyoshi, Hideto, Kita, Kiyoshi
• Format: Article
• Language: English
• Subjects: Alternative oxidase; Animals; Anti-Bacterial Agents - pharmacology; Benzaldehydes - isolation & purification; Benzaldehydes - pharmacology; Cell Membrane - metabolism; Cytochrome b Group - antagonists & inhibitors; Cytochrome b Group - isolation & purification; Cytochrome b Group - metabolism; Cytochromes - antagonists & inhibitors; Cytochromes - metabolism; Cytoplasmic Vesicles - metabolism; Electron Transport Chain Complex Proteins - antagonists & inhibitors; Electron Transport Chain Complex Proteins - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - isolation & purification; Escherichia coli Proteins - metabolism; Inhibitor; Mitochondria - enzymology; Mitochondrial Proteins; Natural antibiotic; Oxidoreductases - antagonists & inhibitors; Oxidoreductases - metabolism; Plant Proteins; Quinol oxidase; Sesquiterpenes - isolation & purification; Sesquiterpenes - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; Verticillium - chemistry
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2008.11.016

To counter antibiotic-resistant bacteria, we screened the Kitasato Institute for Life Sciences Chemical Library with bacterial quinol oxidase, which does not exist in the mitochondrial respiratory chain. We identified five prenylphenols, LL-Z1272β, γ, δ, ɛ and ζ, as new inhibitors for the Escherichia coli cytochrome bd. We found that these compounds also inhibited the E. coli bo-type ubiquinol oxidase and trypanosome alternative oxidase, although these three oxidases are structurally unrelated. LL-Z1272β and ɛ (dechlorinated derivatives) were more active against cytochrome bd while LL-Z1272γ, δ, and ζ (chlorinated derivatives) were potent inhibitors of cytochrome bo and trypanosome alternative oxidase. Thus prenylphenols are useful for the selective inhibition of quinol oxidases and for understanding the molecular mechanisms of respiratory quinol oxidases as a probe for the quinol oxidation site. Since quinol oxidases are absent from mammalian mitochondria, LL-Z1272β and δ, which are less toxic to human cells, could be used as lead compounds for development of novel chemotherapeutic agents against pathogenic bacteria and African trypanosomiasis.