title: Design of an antifungal methionine inhibitor not antagonized by methionine.
abstract: Only a few biosynthetic pathways in fungal cells have been used as antifungal targets. Therefore, the number of antifungals has been limited, and a cross-drug resistance among them has emerged in the therapy of mycoses. Under such circumstances, the identification of an antifungal with a new mode of action is highly desirable. By infecting mice with a mutant of C. albicans deficient in the sulfate assimilation pathway, we have discovered a new target for the discovery of antifungal agents. We have proven that azoxybacilin inhibits the sulfate assimilation pathway by showing its inhibitory activity for [35S]SO4 incorporation into proteins. We have also demonstrated that azoxybacilin was taken up into fungal cells via an active transport system specific for methionine. This sharing of the uptake system with methionine may explain the mechanism by which the antifungal activity of azoxybacilin is antagonized by methionine, and led us to design azoxybacilin derivatives that lack the structural feature of amino acids and, at the same time, have increased hydrophobicity to give higher non-specific permeability through the cell membrane. As a result, we have found that ester derivatives of azoxybacilin were not antagonized by methionine in their uptake, and that they showed antifungal activity independent of methionine. The benzyl ester of azoxybacilin was the same as azoxybacilin in its mode of action, but was not markedly antagonized by methionine at concentrations up to 1 mg/ml. These results suggest that azoxybacilin may not merely interfere with the sulfate assimilation pathway.
authors.affiliation: Nippon Roche Research Center, Kamakura, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Aoki
authors.forename: T
authors.initials: T
authors.lastname: Kamiyama
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: J
authors.initials: J
authors.lastname: Ohwada
authors.forename: M
authors.initials: M
authors.lastname: Arisawa
mesh_terms: D000613:Aminobutyrates / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000472:pathogenicity; D015195:Drug Design; D008715:Methionine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013431:Sulfates / Q000378:metabolism; D014774:Virulence
chemical_list: D000613:Aminobutyrates; D000935:Antifungal Agents; D013431:Sulfates; C089089:azoxybacilin; D008715:Methionine