Developmental Control and Activation of Secondary Metabolism in Streptomyces: A Systematic Review and Meta-Analytical Perspective

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The genus Streptomyces is renowned for producing structurally diverse and clinically important secondary metabolites, yet harnessing its full biosynthetic potential remains a challenge due to complex developmental regulation and largely silent biosynthetic gene clusters. This systematic review and meta-analysis aimed to integrate and quantitatively synthesize experimental evidence linking developmental control, morphological organization, and activation strategies to secondary metabolite production in Streptomyces. A comprehensive literature search was conducted across major biomedical databases to identify peer-reviewed studies published up to 2024. Eligible studies underwent standardized screening, data extraction, and quality assessment. Where appropriate, meta-analyses using random-effects models quantified effect sizes while accounting for inter-study heterogeneity, complemented by narrative synthesis for outcomes unsuitable for pooling. Findings reveal consistent trends across multiple outcomes, despite variability in experimental conditions, strain characteristics, and measurement approaches. Pooled estimates indicate statistically meaningful effects, and sensitivity analyses confirmed robustness. Heterogeneity analyses highlight the influence of morphology, developmental stage, and regulatory interventions on secondary metabolite yield. Most studies demonstrated moderate to high methodological quality, with minimal evidence of publication bias. Overall, this work consolidates fragmented knowledge, clarifies effective strategies for activating cryptic biosynthetic pathways, and emphasizes the critical interplay between developmental differentiation, morphological control, and regulatory modulation. By providing a robust, evidence-based framework, the study informs rational approaches to optimize metabolite production and guides future natural product discovery in Streptomyces.

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