Unlocking Aromatic Polyketides to Combat Antimicrobial Resistance: A Systematic Review and Meta-Analytic Perspective on Biosynthetic Potential and Synthetic Biology Strategies

Antimicrobial resistance (AMR) continues to erode the foundations of modern medicine, threatening once-manageable infections and complicating routine clinical care. In response to this escalating crisis, renewed attention has turned toward microbial natural products—particularly aromatic polyketides—as a source of structurally diverse and biologically potent antimicrobial scaffolds. This systematic review and meta-analysis synthesize current evidence on the antimicrobial efficacy and biosynthetic potential of aromatic polyketides, while contextualizing their discovery within advances in genome mining, metabologenomics, and synthetic biology. Across diverse microbial systems, especially actinomycetes from marine, desert, and other underexplored environments, aromatic polyketides consistently demonstrated strong antimicrobial activity, frequently at low minimum inhibitory concentrations. Meta-analytic pooling under random-effects models confirmed a significant overall effect, despite expected heterogeneity driven by ecological origin, compound structure, and assay variability. Subgroup analyses revealed that rare and environmentally specialized strains often yielded compounds with enhanced potency, reinforcing the importance of ecological novelty in natural product discovery. Beyond bioactivity, this review highlights the expanding toolkit enabling scalable production and rational optimization. Advances in heterologous expression, pathway refactoring, and computational protein modeling are helping to unlock cryptic biosynthetic gene clusters and improve yields, thereby addressing longstanding translational bottlenecks. Collectively, the integrated evidence underscores aromatic polyketides as a renewable and adaptable chemical reservoir with genuine promise for next-generation antimicrobial development. Bridging ecological exploration with genome-enabled engineering strategies may prove essential for revitalizing antibiotic pipelines in the era of global resistance.