Abstract
When used in combination with azole antifungal drugs, cyclooxygenase (COX) inhibitors such as ibuprofen improve antifungal efficacy. We report the conjugation of a chiral antifungal azole pharmacophore to COX inhibitors and the evaluation of activity of 24 hybrids. Hybrids derived from ibuprofen and flurbiprofen were considerably more potent than fluconazole and comparable to voriconazole against a panel of Candida species. The potencies of hybrids composed of an S-configured azole pharmacophore were higher than those with an R-configured pharmacophore. Tolerance, defined as the ability of a subpopulation of cells to grow in the presence of the drug, to the hybrids was lower than to fluconazole and voriconazole. The hybrids were active against a mutant lacking CYP51, the target of azole drugs, indicating that these agents act via a dual mode of action. This study established that azole-COX inhibitor hybrids are a novel class of potent antifungals with clinical potential.
Highlights
Humans and yeast have been evolving along different paths over a period of about a billion years, there is still a significant resemblance between the genomes of human and both friendly and pathogenic yeast.[1−5] Approximately onethird of the genes found in the human genome have counterparts in the genomes of yeast; amino acid sequences of the human proteome overlap by more than 30% with those of the yeast proteome.[6]
Global epidemics are increasingly being caused by drug-resistant fungal pathogens, including Aspergillus fumigatus, Candida glabrata, Cryptococcus neoformans,[5,13−16] and, more recently, Candida auris, a pathogen with the potential for extensive multidrug resistance.[17−20] Notably, infections with drugresistant fungi are associated with mortality rates in the range of 50%, granting them high priority for new drug development.[21−24] An increasingly favored approach to rapidly overcome the shortage in fungal drug targets and drug classes is to enhance the efficacy of existing antifungal drugs through combination therapies.[25]
To synthesize the hybrids composed of an antifungal azole pharmacophore and a COX
Summary
Humans and yeast have been evolving along different paths over a period of about a billion years, there is still a significant resemblance between the genomes of human and both friendly and pathogenic yeast.[1−5] Approximately onethird of the genes found in the human genome have counterparts in the genomes of yeast; amino acid sequences of the human proteome overlap by more than 30% with those of the yeast proteome.[6]. Dose-dependent growth reduction was observed in the presence of free ibuprofen and flurbiprofen, from which hybrids 1 and 5, respectively, were derived This supports that the CYP51-independent antifungal effect of the azole-COX inhibitor hybrids 1 and 5 results from their COX inhibitor segments. The high MIC80 values against the erg3ΔΔ/erg11ΔΔ mutant relative to those against the parent strain support our hypothesis that the contribution to the antifungal activity of the COX-inhibiting segment in these dual-acting agents is modest compared to that of the inhibition of CYP51
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