Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens, including fungal infections. Herein, we show that the simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from that of the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases (NTDs) targeted for elimination by 2030.多种抗感染药物所产生的耐药性问题，清晰凸显了开发新型广谱抗菌剂的迫切需求，尤其是针对由真核寄生病原体（包括真菌病原体）引发的被忽视热带病（Neglected Tropical Diseases, NTDs）的治疗。本研究表明，对最经典的抗真菌药物之一氟康唑（fluconazole）进行有机金属基团的简单修饰，不仅可提升母药的抗菌活性，还可拓宽新型衍生物的应用范围。此类化合物在体内对致病性真菌感染展现出优异疗效，同时对寄生蠕虫亦具有强效活性：其中可引发淋巴丝虫病的布鲁格线虫（Brugia），以及在全球范围内感染数百万人群的土源性线虫之一鞭虫（Trichuris）。值得注意的是，本研究鉴定出的分子靶点表明，此类衍生物的作用机制与母代抗真菌药物存在显著差异，其靶点涉及人类体内不存在的生物合成通路，这为扩充我们对抗耐药性真菌感染以及2030年目标消除的被忽视热带病（NTDs）的武器库提供了巨大潜力。