Augmenting the Activity of Monoterpenoid Phenols against Fungal Pathogens Using 2-Hydroxy-4-methoxybenzaldehyde that Target Cell Wall Integrity

• Published in: International journal of molecular sciences 2015-11, Vol.16 (11), p.26850-26870
• Main Authors: Kim, Jong H, Chan, Kathleen L, Mahoney, Noreen
• Format: Article
• Language: English
• Subjects: Antifungal Agents - pharmacology; antifungal properties; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - enzymology; Aspergillus fumigatus - genetics; benzaldehyde; Benzaldehydes - pharmacology; carvacrol; Cell Wall - drug effects; Cell Wall - enzymology; Cell Wall - genetics; cell walls; Cells; chemosensitization; Dioxoles - pharmacology; Drug Synergism; fludioxonil; Fungi; Gene Expression; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Microbial Sensitivity Tests; mitogen-activated protein kinase; mitogen-activated protein kinase kinase; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Monoterpenes - pharmacology; monoterpenoids; mutants; Mutation; pathogens; Penicillium; Penicillium - drug effects; Penicillium - enzymology; Penicillium - genetics; Phenols; Pyrroles - pharmacology; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Structure-Activity Relationship; structure-activity relationships; thymol; Thymol - pharmacology; yeasts
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms161125988

Disruption of cell wall integrity system should be an effective strategy for control of fungal pathogens. To augment the cell wall disruption efficacy of monoterpenoid phenols (carvacrol, thymol), antimycotic potency of benzaldehyde derivatives that can serve as chemosensitizing agents were evaluated against strains of Saccharomyces cerevisiae wild type (WT), slt2∆ and bck1∆ (mutants of the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase, respectively, in the cell wall integrity pathway). Among fourteen compounds investigated, slt2∆ and bck1∆ showed higher susceptibility to nine benzaldehydes, compared to WT. Differential antimycotic activity of screened compounds indicated “structure-activity relationship” for targeting the cell wall integrity, where 2-hydroxy-4-methoxybenzaldehyde (2H4M) exhibited the highest antimycotic potency. The efficacy of 2H4M as an effective chemosensitizer to monoterpenoid phenols (viz., 2H4M + carvacrol or thymol) was assessed in yeasts or filamentous fungi (Aspergillus, Penicillium) according to European Committee on Antimicrobial Susceptibility Testing or Clinical Laboratory Standards Institute M38-A protocols, respectively. Synergistic chemosensitization greatly lowers minimum inhibitory or fungicidal concentrations of the co-administered compounds. 2H4M also overcame the tolerance of two MAPK mutants (sakA∆, mpkC∆) of Aspergillus fumigatus to fludioxonil (phenylpyrrole fungicide). Collectively, 2H4M possesses chemosensitizing capability to magnify the efficacy of monoterpenoid phenols, which improves target-based (viz., cell wall disruption) antifungal intervention.