Microbial Steroids: Novel Frameworks and Bioactivity Profiles

Microorganisms have emerged as prolific and versatile producers of steroidal natural products, displaying a remarkable capacity for structural diversification that extends far beyond classical sterol frameworks. This review critically examines steroidal metabolites isolated from microbial sources, with a particular emphasis on marine-derived and endophytic fungi belonging to the genera Aspergillus and Penicillium, alongside selected bacterial and lesser-studied fungal taxa. Comparative analysis reveals that these organisms repeatedly generate distinctive steroid scaffolds, including highly oxygenated ergostanes, secosteroids, rearranged polycyclic systems, and hybrid architectures arising from oxidative cleavage, cyclization, and Diels–Alder-type transformations. While many reported compounds exhibit cytotoxic, anti-inflammatory, antimicrobial, or enzyme-inhibitory activities, the biological relevance of these metabolites varies considerably, highlighting the need to distinguish broadly recurring bioactivities from isolated or strain-specific observations. By integrating structural classification with biosynthetic considerations and bioactivity trends, this review identifies key steroidal frameworks that recur across taxa and appear particularly promising for further pharmacological investigation. In addition, current gaps in mechanistic understanding and compound prioritization are discussed. Finally, emerging strategies such as genome mining, biosynthetic gene cluster analysis, co-culture approaches, and synthetic biology are highlighted as powerful tools to unlock the largely untapped potential of microbial genomes for the discovery of novel steroidal scaffolds. Together, this synthesis underscores the importance of microorganisms as a dynamic and expandable source of structurally unique and biologically relevant steroids, and provides a framework to guide future discovery-driven and mechanism-oriented research in the field.