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An Antifungal Combination Matrix Identifies a Rich Pool of Adjuvant Molecules that Enhance Drug Activity against Diverse Fungal Pathogens.

Abstract：

:There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil with ∼3,600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole-resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode of action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Additional tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens.

journal_name

Cell Rep

journal_title

Cell reports

authors

Robbins N,Spitzer M,Yu T,Cerone RP,Averette AK,Bahn YS,Heitman J,Sheppard DC,Tyers M,Wright GD

doi

10.1016/j.celrep.2015.10.018

subject

Has Abstract

pub_date

2015-11-17 00:00:00

pages

1481-1492

issue

7

issn

2211-1247

pii

S2211-1247(15)01172-9

journal_volume

13

pub_type

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