Kim Jong H, Chan Kathleen L, Mahoney Noreen
Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA.
Int J Mol Sci. 2015 Nov 10;16(11):26850-70. 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), 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.
破坏细胞壁完整性系统应该是控制真菌病原体的一种有效策略。为了增强单萜酚类（香芹酚、百里香酚）对细胞壁的破坏效果，对可作为化学增敏剂的苯甲醛衍生物针对酿酒酵母野生型（WT）、slt2Δ和bck1Δ（分别为细胞壁完整性途径中丝裂原活化蛋白激酶（MAPK）和MAPK激酶激酶的突变体）菌株的抗真菌效力进行了评估。在所研究的14种化合物中，与WT相比，slt2Δ和bck1Δ对9种苯甲醛表现出更高的敏感性。筛选出的化合物的不同抗真菌活性表明了针对细胞壁完整性的“构效关系”，其中2-羟基-4-甲氧基苯甲醛（2H4M）表现出最高的抗真菌效力。根据欧洲抗菌药物敏感性测试委员会或临床实验室标准协会M38-A方案，分别在酵母或丝状真菌（曲霉属、青霉属）中评估了2H4M作为单萜酚类（即2H4M+香芹酚或百里香酚）有效化学增敏剂的效果。协同化学增敏作用大大降低了共同给药化合物的最低抑菌或杀菌浓度。2H4M还克服了烟曲霉的两个MAPK突变体（sakAΔ、mpkCΔ）对氟啶菌酰胺（苯基吡咯类杀菌剂）的耐受性。总体而言，2H4M具有化学增敏能力，可放大单萜酚类的功效，从而改善基于靶点（即细胞壁破坏）的抗真菌干预。
