Abstract
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.
Highlights
Filamentous fungi in the genus Aspergillus are ubiquitous opportunistic pathogens, which are most notable as causative agents of highly enervating human diseases such as aspergillosis [1]
Results showed that: (1) 2H4M functioned as an effective antifungal chemosensitizer to augment the potency of monoterpenoid phenols; and (2) 2H4M overcame the tolerance of A. fumigatus mitogen-activated protein kinase (MAPK) mutants to fludioxonil, a phenylpyrrole fungicide
Test benzaldehydes were further classified into three groups based on the level of antifungal potency against bck1∆ and slt2∆ mutants as follows: Group 1, 2H4M, 2-methyl-4-methoxybenzaldehyde, 3,5-dimethoxybenzaldehyde (3,5-DMBA), 2,3-dimethoxybenzaldehyde (2,3-DMBA) (Complete growth inhibition of bck1∆ and slt2∆ mutants at 5.0 mM cutoff); Group 2, 2,5-dimethoxybenzaldehyde (2,5-DMBA), 2-methoxybenzaldehyde, 2,4-dimethoxybenzaldehyde (2,4-DMBA), 3-methoxybenzaldehyde, 4-methoxybenzaldehyde [Moderate growth inhibition of bck1∆ and slt2∆ mutants at 5.0 mM cutoff]; and Group 3, 2,4,5-trimethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde (3,4-DMBA), 4-hydroxy-3-methoxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde (4H2M), 3,5-dimethoxy-4-hydroxybenzaldehyde, BA (No growth inhibition of bck1∆ and slt2∆ mutants at 5.0 mM cutoff) (Table 3)
Summary
Filamentous fungi in the genus Aspergillus are ubiquitous opportunistic pathogens, which are most notable as causative agents of highly enervating human diseases such as aspergillosis [1]. Cell wall targeting drugs (e.g., echinocandins) could be administered as broad-spectrum antimycotic agents for control of filamentous or yeast fungal pathogens, including species of Candida ([23] and references therein). Development of new drugs or intervention strategies is continually required for effective control of fungal pathogens, especially the strains exhibiting drug or fungicide resistance. Antifungal chemosensitization is an intervention scheme for effective control of pathogenic fungi, where co-application of a selected natural or synthetic compound (viz., a chemosensitizer or a chemosensitizing agent) with a conventional antifungal drug can intensify the drug efficacy [31]. Two S. cerevisiae cell wall integrity mutants (bck1∆, slt2∆), where genes in cell wall integrity MAPK pathway were deleted (Table 2), were examined to evaluate the efficacy of targeting cell wall integrity via natural product-based antifungal chemosensitization (namely, monoterpenoid phenols + 2H4M). Results showed that: (1) 2H4M functioned as an effective antifungal chemosensitizer to augment the potency of monoterpenoid phenols; and (2) 2H4M overcame the tolerance of A. fumigatus MAPK mutants (sakA∆, mpkC∆) to fludioxonil, a phenylpyrrole fungicide
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