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by claude@2026-07, 2026-07-05
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The paper studied how Trichophyton rubrum strains with deletions of specific cyp51 isozyme genes (Δcyp51A, Δcyp51B, and wild-type) respond to azole antifungals with different cyp51 selectivities, including assessing synergy when two isozyme-selective agents are combined. It found distinct susceptibility patterns across antifungals for Δcyp51A versus Δcyp51B, with fluconazole, sulconazole, and imazalil showing relatively increased activity against Δcyp51A, while prochloraz showed relatively increased activity against Δcyp51B. The dual-azole combinations produced synergistic effects against the wild-type strain and a ku80-knockout parent strain, but not against individual single-cyp51 knockout mutants; a key limitation is that synergy depended on intact dual-isozyme genetic backgrounds rather than being observed in the single-knockout strains. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Pathogenic fungi pose significant societal challenges. The limited availability of therapeutic targets due to the eukaryotic nature of fungi emphasizes the importance of available drug targets such as Cyp51, a crucial enzyme in ergosterol biosynthesis, inhibited by azole antifungals. This study explored the susceptibility patterns of azole antifungals against Cyp51 isozyme deletion strains (Δ cyp51A and Δ cyp51B ) in Trichophyton rubrum , the predominant dermatophyte species. Distinct susceptible patterns were observed among azole antifungals for Δ cyp51A and Δ cyp51B . Although most azole antifungal agents exhibited increased antifungal activity against Δ cyp51A , select agents demonstrated increased antifungal activity against Δ cyp51B . Remarkably, fluconazole, sulconazole, and imazalil exhibited relatively increased activity against Δ cyp51A , whereas prochloraz demonstrated increased activity against Δ cyp51B . Combining these isozyme-selective agents exerted synergistic effects against the wild-type strain and the parent ku80 -knockout strain but not against individual Cyp51 knockout mutants. Hence, the two Cyp51 isozymes, Cyp51A and Cyp51B, may be inhibited by distinct azole antifungals, exerting a synergistic effect with the dual azole antifungal combination. This synergistic effect was also observed on another fungal species, Aspergillus welwitschiae , which also has two Cyp51 isozymes. These data demonstrate that combining azole antifungals with different Cyp51 isozyme selectivities exerts synergistic effects against fungi possessing multiple Cyp51 isozymes. This study proposes a novel therapeutic approach for addressing fungal infections through the combination of antifungal drugs that inhibit the same enzymatic activity but exhibit different isozyme selectivity. It also emphasizes the potential for developing drugs targeting specific isozymes, a previously underutilized approach in the realm of antifungal drug development.
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Abstract
Pathogenic fungi pose significant societal challenges. The limited availability of therapeutic targets due to the eukaryotic nature of fungi emphasizes the importance of available drug targets such as Cyp51, a crucial enzyme in ergosterol biosynthesis, inhibited by azole antifungals. This study explored the susceptibility patterns of azole antifungals against Cyp51 isozyme deletion strains (Δcyp51A and Δcyp51B) in Trichophyton rubrum, the predominant dermatophyte species. Distinct susceptible patterns were observed among azole antifungals for Δcyp51A and Δcyp51B. Although most azole antifungal agents exhibited increased antifungal activity against Δcyp51A, select agents demonstrated increased antifungal activity against Δcyp51B. Remarkably, fluconazole, sulconazole, and imazalil exhibited relatively increased activity against Δcyp51A, whereas prochloraz demonstrated increased activity against Δcyp51B. Combining these isozyme-selective agents exerted synergistic effects against the wild-type strain and the parent ku80-knockout strain but not against individual Cyp51 knockout mutants. Hence, the two Cyp51 isozymes, Cyp51A and Cyp51B, may be inhibited by distinct azole antifungals, exerting a synergistic effect with the dual azole antifungal combination. This synergistic effect was also observed on another fungal species, Aspergillus welwitschiae, which also has two Cyp51 isozymes. These data demonstrate that combining azole antifungals with different Cyp51 isozyme selectivities exerts synergistic effects against fungi possessing multiple Cyp51 isozymes. This study proposes a novel therapeutic approach for addressing fungal infections through the combination of antifungal drugs that inhibit the same enzymatic activity but exhibit different isozyme selectivity. It also emphasizes the potential for developing drugs targeting specific isozymes, a previously underutilized approach in the realm of antifungal drug development.
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