Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei

Chiatogu Onyewu, Jill R Blankenship, Maurizio Del Poeta, Joseph Heitman

Research output: Contribution to journalArticle

179 Citations (Scopus)

Abstract

Azoles target the ergosterol biosynthetic enzyme lanosterol 14α-demethylase and are a widely applied class of antifungal agents because of their broad therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately, azoles are generally fungistatic and resistance to fluconazole is emerging in several fungal pathogens. We recently established that the protein phosphatase calcineurin allows survival of Candida albicans during the membrane stress exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal activity, and mutant strains lacking calcineurin are markedly hypersensitive to azoles. Here we establish that drugs targeting other enzymes in the ergosterol biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic synergistic antifungal activity against wild-type C. albicans when used in conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance abolishes drug synergism. Additionally, we provide evidence of drug synergy between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or terbinafine against wild-type C. albicans. These drug combinations also exert synergistic effects against two other Candida species, C. glabrata and C. krusei, which are known for intrinsic or rapidly acquired resistance to azoles. These studies demonstrate that the activity of non-azole antifungal agents that target ergosterol 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.

Original languageEnglish (US)
Pages (from-to)956-964
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume47
Issue number3
DOIs
StatePublished - Mar 3 2003

Fingerprint

Candida glabrata
Ergosterol
Azoles
terbinafine
Tacrolimus
Candida albicans
Candida
Calcineurin
Antifungal Agents
Cyclosporine
Fungal Drug Resistance
Drug Synergism
Tacrolimus Binding Protein 1A
Lanosterol
Tacrolimus Binding Proteins
Fluconazole
Phosphoprotein Phosphatases
Biosynthetic Pathways
Drug Combinations
Enzymes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei. / Onyewu, Chiatogu; Blankenship, Jill R; Del Poeta, Maurizio; Heitman, Joseph.

In: Antimicrobial Agents and Chemotherapy, Vol. 47, No. 3, 03.03.2003, p. 956-964.

Research output: Contribution to journalArticle

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