Friberg Louise I M, Kavanagh Angela, Amado Maite, Lowe Gabrielle, Zuegg Johannes, Novais de Paula Michelle, Onawole Abdulmujeeb, Floyd Holly E E, Kravchenko Angelina N, Guan Davy, Elliott Alysha G, Kuchar Julia, Mohr Fabian, Luzina Olga, Salakhutdinov Nariman, Volcho Konstantin, Farrukh Hafiz S U B, Kalsoom Umme, Saleem Rahman S Z, Blanchfield Joanne, Blaskovich Mark A T, Hansford Karl A
Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland St Lucia QLD Australia
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences Moscow 119991 Russia.
RSC Med Chem. 2025 Apr 7. doi: 10.1039/d4md00677a.
The urgent need for novel antifungal drugs is underscored by the limited number of antifungal agents in clinical development and the global spread of fungal resistance. This study highlights the potential of organoselenium compounds as a new source of scaffolds with promising antifungal activity against a variety of fungal strains. Analysis of over 300 000 compounds screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antibacterial and antifungal activity identified 233 organoselenium derivatives. A remarkable 33% (77) of these exhibited antifungal activity against two representative strains of and , in contrast to only 2% of the non-selenium-containing organic compounds tested by CO-ADD. Of these compounds that displayed antifungal activity (MIC < 16 μg mL), 87% did not exhibit cytotoxicity against mammalian cell lines or haemolytic properties at similar concentrations, compared to only 35% of the organic 'hits'. A subset of these 69 compounds was further evaluated against three clinically relevant fungal strains that often exhibit resistance to current antifungals (, MDR , and ), and generally retained good activity. Lastly, we compared a handful of matched sulfur and selenium compounds which further highlighted the beneficial impact of this bioisosteric conversion on antifungal activity.
临床开发中的抗真菌药物数量有限以及真菌耐药性在全球范围内的传播，凸显了对新型抗真菌药物的迫切需求。本研究强调了有机硒化合物作为一种新的支架来源的潜力，其对多种真菌菌株具有有前景的抗真菌活性。对由开放抗菌药物发现社区（CO-ADD）筛选的超过300000种化合物的抗菌和抗真菌活性进行分析，鉴定出233种有机硒衍生物。其中有33%（77种）对两种代表性的 和 菌株表现出抗真菌活性，相比之下，CO-ADD测试的不含硒的有机化合物中只有2%有此活性。在这些显示出抗真菌活性（MIC<16μg/mL）的化合物中，87%在相似浓度下对哺乳动物细胞系未表现出细胞毒性或溶血特性，而有机“活性化合物”中只有35%如此。对这69种化合物中的一部分进一步针对三种临床上相关的、通常对当前抗真菌药物耐药的真菌菌株（ 、多重耐药 以及 ）进行评估，它们总体上保持了良好的活性。最后，我们比较了一些匹配的硫和硒化合物，这进一步突出了这种生物电子等排体转换对抗真菌活性的有益影响。
