Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases.
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-Z1272beta, gamma, delta, epsilon and zeta, 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-Z1272beta and epsilon (dechlorinated derivatives) were more active against cytochrome bd while LL-Z1272gamma, delta, and zeta (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-Z1272beta and delta, 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.
Mogi
Tatsushi
T
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. tmogi@m.u-tokyo.ac.jp
Ui
Hideaki
H
Shiomi
Kazuro
K
Omura
Satoshi
S
Miyoshi
Hideto
H
Kita
Kiyoshi
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000302:isolation & purification / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D003573:Cytochrome b Group / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D003580:Cytochromes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010940:Plant Proteins; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology; D020172:Verticillium / Q000737:chemistry; D000099188:Alternative Oxidase
D000900:Anti-Bacterial Agents; D001547:Benzaldehydes; D003573:Cytochrome b Group; D003580:Cytochromes; D045222:Electron Transport Chain Complex Proteins; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D012717:Sesquiterpenes; D000099188:Alternative Oxidase; C000603094:LL-Z1272beta; C017168:cytochrome bo, E coli; C432586:ubiquinol oxidase; C040077:cytochrome bd terminal oxidase complex, E coli