@entity12364 biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against XXXX , @entity7408 , and Candida krusei.

@entity12364 @entity8974 @entity137 @entity2380 @entity7408 @entity5638 @entity18749 @entity56025 @entity5132 @entity205 @entity1140 @entity8201 @entity72646
@entity8201 target the @entity12364 biosynthetic enzyme @entity18749 14alpha-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low @entity137 . Unfortunately, @entity8201 are generally fungistatic and resistance to @entity2380 is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of @entity5132 during the membrane stress exerted by @entity8201 . The calcineurin inhibitors @entity205 (CsA) and @entity1140 ( @entity1140 ) are dramatically synergistic with @entity8201 , resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to @entity8201 . Here we establish that drugs targeting other enzymes in the @entity12364 biosynthetic pathway (terbinafine and @entity56025 ) also exhibit dramatic synergistic antifungal activity against wild-type @entity5132 when used in conjunction with CsA and @entity1140 . Similarly, @entity5132 mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and @entity56025 . The @entity1140 binding protein FKBP12 is required for @entity1140 synergism with @entity12364 biosynthesis inhibitors, and a calcineurin mutation that confers @entity1140 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive @entity1140 analog @entity72646 and @entity56025 or @entity8974 against wild-type @entity5132 . These drug combinations also exert synergistic effects against two other Candida species, @entity7408 and C. krusei, which are known for intrinsic or rapidly acquired resistance to @entity8201 . These studies demonstrate that the activity of non- @entity5638 antifungal agents that target @entity12364 biosynthesis can be enhanced by inhibition of the calcineurin signaling pathway, extending their spectrum of action and providing an alternative approach by which to overcome antifungal drug resistance.
