White Paper — The Beauty of Microbial Natural Products: Selective Polypharmacology ≠ Promiscuity

For decades, the 'one‑drug, one‑target' paradigm shaped discovery strategies. Although this approach yielded many important medicines, it often underperforms against complex, multi‑factorial diseases in which networks of proteins and pathways adapt to single‑node blockade. Network pharmacology reframes this challenge by embracing polypharmacology—intentional, selective engagement of multiple targets—to achieve more durable efficacy. Polypharmacology is frequently conflated with promiscuous, non‑specific binding. This white paper clarifies that distinction and argues that microbial natural products (NPs), refined by evolution, provide exemplary scaffolds for potent yet selective multi‑target modulation. We review definitions, pitfalls (e.g., PAINS and colloidal aggregation), representative case studies (rapamycin, cyclosporin A, tacrolimus), and enabling technologies (genome/mining, semisynthesis, AI and chemoproteomics). We also correct common statistics: across 1981–2019, ~65% of small‑molecule anticancer drugs are natural‑product‑derived or inspired when synthetic mimics are included, and about 60% of antibacterials are based on or derived from natural products; for anti‑infectives as a broader class the figure is ~42%. Beyond classic genome-mining and synthetic library screening, we also highlight industrial-scale microbiome mining as a practical route to privileged, stereochemically rich scaffolds that enable selective polypharmacology. Taken together, the evidence supports microbial NPs as privileged