Azhari Muhammad, Merliani Novi, Singgih Marlia, Arai Masayoshi, Julianti Elin
School of Pharmacy, Bandung Institute of Technology, Jl. Ganesha No. 10, Bandung 40132, Indonesia.
Laboratory of Natural Products for Drug Discovery, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Osaka 565-0871, Japan.
Mar Drugs. 2025 Jul 3;23(7):279. doi: 10.3390/md23070279.
Tuberculosis (TB) poses a persistent global health threat exacerbated by the emergence of drug-resistant strains; hence, there is a continuous quest for novel antimicrobial agents. Despite efforts to develop effective therapies, existing treatments require a relatively long duration of therapy to eradicate the pathogen due to its virulence factors, pathogenesis patterns, and ability to enter dormant states. This can lead to a higher risk of treatment failure due to poor patient adherence to the complex regimen. As a result, considerable research is necessary to identify alternative antituberculosis agents. The marine environment, particularly marine-derived fungi, has recently gained interest due to its potential as an abundant source of bioactive natural products. This review covers 19 genera of marine-derived fungi and 139 metabolites, 131 of which exhibit antimycobacterial activity. The integrated dataset pinpoints the fungal genera and chemical classes that most frequently yield potent antimycobacterial hits while simultaneously exposing critical gaps, such as the minimal evaluation of compounds against dormant bacilli and the presence of underexplored ecological niches and fungal genera. Several compounds exhibit potent activity through uncommon mechanisms, including the inhibition of mycobacterial protein tyrosine phosphatases (MptpB/MptpA), protein kinase PknG, ATP synthase and the disruption of mycobacterial DNA via G-quadruplex stabilization. Structure-activity relationship (SAR) trends are highlighted for the most potent agents, illuminating how specific functional groups underpin target engagement and potency. This review also briefly proposes a dereplication strategy and approaches for toxicity mitigation in the exploration of marine-derived fungi's natural products. Through this analysis, we offer insights into the potency and challenges of marine-derived fungi's natural products as hit compounds or scaffolds for further antimycobacterial research.
结核病(TB)对全球健康构成持续威胁,耐药菌株的出现使其进一步恶化;因此,人们一直在不断寻求新型抗菌药物。尽管致力于开发有效的治疗方法,但由于病原体的毒力因子、发病机制模式以及进入休眠状态的能力,现有治疗方法需要相对较长的疗程来根除病原体。这可能导致因患者对复杂治疗方案依从性差而出现治疗失败的风险更高。因此,有必要进行大量研究以确定替代抗结核药物。海洋环境,特别是海洋来源的真菌,因其作为生物活性天然产物丰富来源的潜力,最近受到了关注。本综述涵盖了19个海洋来源真菌属和139种代谢产物,其中131种具有抗分枝杆菌活性。综合数据集确定了最常产生有效抗分枝杆菌活性成分的真菌属和化学类别,同时也揭示了关键差距,例如对休眠杆菌的化合物评估极少,以及存在未充分探索的生态位和真菌属。几种化合物通过不常见的机制表现出强大活性,包括抑制分枝杆菌蛋白酪氨酸磷酸酶(MptpB/MptpA)、蛋白激酶PknG、ATP合酶以及通过稳定G-四链体破坏分枝杆菌DNA。突出了最有效药物的构效关系(SAR)趋势,阐明了特定官能团如何支撑靶点结合和活性。本综述还简要提出了一种在探索海洋来源真菌天然产物时的去重复策略和减轻毒性的方法。通过这种分析,我们深入了解了海洋来源真菌天然产物作为进一步抗分枝杆菌研究的活性成分或骨架的效力和挑战。