Augmenting the Activity of Monoterpenoid Phenols against Fungal Pathogens Using 2-Hydroxy-4-methoxybenzaldehyde that Target Cell Wall Integrity.
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), slt2Δ and bck1Δ (mutants of the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase, respectively, in the cell wall integrity pathway). Among fourteen compounds investigated, slt2Δ and bck1Δ 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 (sakAΔ, mpkCΔ) 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.
['Kim|Jong H|JH|', 'Chan|Kathleen L|KL|', 'Mahoney|Noreen|N|']
D000935:Antifungal Agents D001232:Aspergillus fumigatus D001547:Benzaldehydes D002473:Cell Wall D000081007:Cymenes D004149:Dioxoles D004357:Drug Synergism D015870:Gene Expression D020930:MAP Kinase Kinase Kinases D008826:Microbial Sensitivity Tests D020928:Mitogen-Activated Protein Kinases D039821:Monoterpenes D009154:Mutation D010407:Penicillium D011758:Pyrroles D012441:Saccharomyces cerevisiae D029701:Saccharomyces cerevisiae Proteins D013329:Structure-Activity Relationship D013943:Thymol
monoterpenoids cell wall integrity antimycotic benzaldehydes chemosensitization Saccharomyces cerevisiae filamentous fungi mycotoxins signal transduction synergism