Harnessing Rubiaceae Plant Endophytic Fungi: A Comprehensive Review of Novel Antimicrobial Compounds for Drug Discovery

Abstract

Antimicrobial resistance (AMR) continues to threaten the effectiveness of existing therapies, driving the urgent search for novel therapeutic leads from nature. Rubiaceae plant-associated endophytic fungi are increasingly recognized as valuable producers of structurally diverse secondary metabolites with antibacterial, antifungal, and antimycobacterial activities. Unlike previous reviews that primarily focus on bioactive compounds, this narrative-critical review integrates ecological factors influencing endophytic diversity with advanced strategies to awaken cryptic biosynthetic pathways. We systematically evaluate approaches including One Strain-Many Compounds (OSMAC), co-culture, chemical and epigenetic elicitation, genome-guided discovery, and heterologous expression. Furthermore, this review critically analyzes pharmacological metrics, specifically minimum inhibitory concentration (MIC), cytotoxicity, Selectivity Index (SI), mechanisms of action, and the potential of fungal metabolites as antibiotic adjuvants. Current evidence suggests that the clinical development of these natural products is constrained by methodological inconsistencies, a lack of animal model testing, insufficient pharmacokinetic profiling, and large-scale manufacturing hurdles. Future progress in drug discovery will heavily depend on adopting standardized evaluation criteria and comprehensive pharmacological screening to successfully transform these endophytic metabolites into viable clinical candidates.