Drug-resistant fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (Gly_0.8Nap_0.2)₂₀, which targets both the fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (Gly_0.8Nap_0.2)₂₀ shows superior performance compared with amphotericin B by showing not only potent antifungal activities but also high antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (Gly_0.8Nap_0.2)₂₀ exhibits promising in vivo therapeutic activities against drug-resistant Candida albicans in mouse models of skin abrasion, corneal infection and systemic infection. This study shows that dual-targeting antifungal compounds may be effective in combating drug-resistant fungal pathogens and mitigating fungal resistance.

耐药真菌感染对人类健康构成重大威胁。双靶向化合物对单一病原体具有多个靶点，为对抗耐药病原体提供了一种有效的方法，尽管确保有效的活性和高选择性仍然是一个挑战。在这里，我们提出了设计抗真菌化合物的双靶向策略。我们将 DNA 结合萘基团作为疏水部分纳入模拟宿主防御肽的聚 (2-恶唑啉) 中。这产生了一种化合物 (Gly _0.8 Nap _0.2 ) ₂₀，它同时靶向真菌膜和 DNA。该化合物可杀死多重耐药真菌的临床菌株，包括念珠菌、新型隐球菌、格特隐球菌和烟曲霉。 (Gly _0.8 Nap _0.2 ) ₂₀与两性霉素 B 相比，不仅具有有效的抗真菌活性，而且还具有高抗真菌选择性，因此表现出优越的性能。该化合物也不会引起抗菌素耐药性。此外，(Gly _0.8 Nap _0.2 ) ₂₀在皮肤擦伤、角膜感染和全身感染的小鼠模型中表现出针对耐药白色 念珠菌的有前景的体内治疗活性。这项研究表明，双靶点抗真菌化合物可能有效对抗耐药真菌病原体并减轻真菌耐药性。