School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 6997801, Israel.
The Wohl Drug Discovery institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 7610001, Israel.
J Am Chem Soc. 2022 Apr 6;144(13):5965-5975. doi: 10.1021/jacs.2c00269. Epub 2022 Mar 29.
Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3,4-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-resistant strains. The dehydroxylated compounds did not significantly affect the viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistant strains, which contain mutations in the 1 and/or 2 genes of the parental strains, identified amino acids of the Fks proteins that are likely to reside in proximity to the l-homotyrosine residue of the bound drug. This study describes the first example of a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal of antifungal drugs, against resistant fungal pathogens.
每年，真菌病原体引起的感染导致约 160 万人死亡，并影响全球超过 10 亿人的健康。最近开发的抗真菌药物包括棘白菌素，它非竞争性地抑制β-葡聚糖合酶，这是一种膜结合蛋白复合物，催化真菌细胞壁主要多糖成分的形成。对棘白菌素的耐药性是由编码β-葡聚糖合酶复合物催化亚基的基因中的突变赋予的。在这里，我们报告说，选择性去除棘白菌素类药物阿尼达fungin 和 rezafungin 中 3,4-二羟基-l-高酪氨酸的非蛋白氨基酸的苄醇，恢复了它们对大量棘白菌素耐药菌株的功效。去羟化化合物对人源细胞培养系的活力没有显著影响。对去羟化棘白菌素类药物对含有亲本菌株 1 号和/或 2 号基因突变的耐药菌株的疗效分析，确定了 Fks 蛋白中可能与结合药物的 l-高酪氨酸残基接近的氨基酸。本研究描述了恢复棘白菌素类药物疗效的化学修饰策略的第一个例子，这些药物在抗真菌药物武器库中具有重要地位，可对抗耐药真菌病原体。
