False Novelty in Antibacterial Natural-Product Discovery: Rediscovery, Structural Misassignment, and a Checkpoint Framework for Early Verification.

Antimicrobial resistance is outpacing antibacterial innovation, yet most explanations for the shrinking pipeline emphasize downstream economic and regulatory attrition. This review identifies an underexamined upstream bottleneck: the unreliable recognition of genuine chemical novelty when a natural-product hit is first encountered. It advances a unifying framework-false novelty-that treats two conventionally separate failures-the rediscovery of known metabolites and the structural misassignment of genuinely new ones-as coordinate manifestations of a single diagnostic failure, an integration rarely made explicit. Eleven independently verified cases from 2019 to 2025, spanning three rediscoveries and eight misassignments, demonstrate that both failures persist under modern instrumentation. Their persistence, therefore, appears to reflect inconsistent workflow adoption more than a lack of technical capability, since dereplication and computational structure-verification tools mature enough to intercept both are already available. The review translates this diagnosis into a resource-conscious, three-checkpoint verification workflow that matches each failure mode to an appropriate remedy at the discovery stage, where correction is cheapest. Recognizing novelty earlier offers a tractable route to conserving scarce discovery-stage resources.