Vargas-Junior Valdemir, Guimarães Ana Carolina Ramos, Caffarena Ernesto Raul, Antunes Deborah
Laboratory for Applied Genomics and Bioinnovations, Oswaldo Cruz Institute (IOC - FIOCRUZ), Rio de Janeiro 21040-900, Brazil.
Computational Biophysics and Molecular Modeling Group, Scientific Computing Program (PROCC - FIOCRUZ), Rio de Janeiro 21040-360, Brazil.
ACS Omega. 2024 Dec 10;9(51):50134-50146. doi: 10.1021/acsomega.4c00158. eCollection 2024 Dec 24.
The rising incidence of fungal infections coupled with limited treatment options underscores the urgent need for novel antifungal therapies. Riboswitches, particularly thiamin pyrophosphate (TPP) class, have emerged as promising antimicrobial targets. This study presents a comprehensive genome-wide analysis of TPP riboswitches in 156 medically relevant fungi utilizing advanced covariance models (CMs) tailored for fungal sequences. Our investigation identified 378 conserved TPP riboswitch sequences distributed across 140 distinct species, revealing a broader prevalence than that previously recognized. Notably, we provide evidence for a novel putative group of TPP riboswitches, designated TPPsw, associated with sugar transporters in Mucoromycota and Basidiomycota. This group exhibits distinctive structural features while maintaining key TPP-binding motifs, potentially expanding our understanding of the riboswitch diversity in fungi. Our analysis highlights the impact of P3 stem variability on riboswitch detection and characterization, demonstrating the superiority of fungal-specific CMs over generic models. We observed multiple TPP riboswitches in over 50% of the examined species, including clinically significant pathogens involved in aspergillosis and mucormycosis. Remarkably, , a species associated with COVID-19 coinfections, harbors six distinct TPP riboswitch sequences, whereas the extremophilic black fungus possesses nine. These findings not only elucidate the diverse distribution of TPP riboswitches in pathogenic fungi but also emphasize their potential as multifaceted targets for antifungal drug development. By addressing key limitations of previous detection methods and providing insights into riboswitch structural diversity, this study lays a foundation for future investigations into riboswitch-mediated regulation in fungi and the development of novel antifungal strategies.
真菌感染发病率的上升以及治疗选择的有限性凸显了对新型抗真菌疗法的迫切需求。核糖开关，特别是焦磷酸硫胺素（TPP）类，已成为有前景的抗菌靶点。本研究利用针对真菌序列定制的先进协方差模型（CMs），对156种医学相关真菌中的TPP核糖开关进行了全面的全基因组分析。我们的调查确定了分布在140个不同物种中的378个保守TPP核糖开关序列，揭示了比以前认识到的更广泛的普遍性。值得注意的是，我们为一组新的推定TPP核糖开关提供了证据，称为TPPsw，与毛霉亚门和担子菌亚门中的糖转运蛋白相关。该组具有独特的结构特征，同时保留关键的TPP结合基序，可能会扩展我们对真菌中核糖开关多样性的理解。我们的分析突出了P3茎变异性对核糖开关检测和表征的影响，证明了真菌特异性CMs优于通用模型。我们在超过50%的被检查物种中观察到多个TPP核糖开关，包括参与曲霉病和毛霉病的具有临床意义的病原体。值得注意的是，与COVID-19合并感染相关的物种 含有六个不同的TPP核糖开关序列，而嗜极端环境的黑木耳 则有九个。这些发现不仅阐明了TPP核糖开关在致病真菌中的多样分布，还强调了它们作为抗真菌药物开发多方面靶点的潜力。通过解决先前检测方法的关键局限性并提供对核糖开关结构多样性的见解，本研究为未来对真菌中核糖开关介导的调控以及新型抗真菌策略的开发奠定了基础。
