Department of Medicine, Medical Microbiology and Immunology.
Pharmaceutical Sciences Division, and.
J Clin Invest. 2021 Mar 1;131(5). doi: 10.1172/JCI145123.
The emergence of drug-resistant fungi has prompted an urgent threat alert from the US Centers for Disease Control (CDC). Biofilm assembly by these pathogens further impairs effective therapy. We recently identified an antifungal, turbinmicin, that inhibits the fungal vesicle-mediated trafficking pathway and demonstrates broad-spectrum activity against planktonically growing fungi. During biofilm growth, vesicles with unique features play a critical role in the delivery of biofilm extracellular matrix components. As these components are largely responsible for the drug resistance associated with biofilm growth, we explored the utility of turbinmicin in the biofilm setting. We found that turbinmicin disrupted extracellular vesicle (EV) delivery during biofilm growth and that this impaired the subsequent assembly of the biofilm matrix. We demonstrated that elimination of the extracellular matrix rendered the drug-resistant biofilm communities susceptible to fungal killing by turbinmicin. Furthermore, the addition of turbinmicin to otherwise ineffective antifungal therapy potentiated the activity of these drugs. The underlying role of vesicles explains this dramatic activity and was supported by phenotype reversal with the addition of exogenous biofilm EVs. This striking capacity to cripple biofilm assembly mechanisms reveals a new approach to eradicating biofilms and sheds light on turbinmicin as a promising anti-biofilm drug.
耐药真菌的出现促使美国疾病控制与预防中心（CDC）发出紧急威胁警报。这些病原体的生物膜组装进一步削弱了有效的治疗效果。我们最近发现了一种抗真菌药物，即涡轮霉素，它可以抑制真菌囊泡介导的运输途径，并对浮游生长的真菌表现出广谱活性。在生物膜生长过程中，具有独特特征的囊泡在输送生物膜细胞外基质成分方面起着关键作用。由于这些成分在很大程度上与生物膜生长相关的耐药性有关，我们探索了涡轮霉素在生物膜环境中的应用。我们发现涡轮霉素在生物膜生长过程中破坏了细胞外囊泡（EV）的输送，从而破坏了生物膜基质的后续组装。我们证明，消除细胞外基质使耐药性生物膜群落易受涡轮霉素的真菌杀伤。此外，向其他无效的抗真菌治疗中添加涡轮霉素增强了这些药物的活性。囊泡的潜在作用解释了这种显著的活性，并通过添加外源性生物膜 EV 来逆转表型得到了支持。这种破坏生物膜组装机制的惊人能力揭示了一种消除生物膜的新方法，并凸显了涡轮霉素作为一种有前途的抗生物膜药物的潜力。
