Antibiotic pipeline attrition: rational design strategies inspired by clinical candidates that failed to reach FDA approval

The global antibiotic pipeline has historically faced substantial attrition, with numerous clinical candidates failing to achieve FDA approval despite reaching advanced development phases. These failures stem from a wide range of factors, including inadequate pharmacokinetic and pharmacodynamic profiles, systemic toxicity, poor bioavailability, chemical instability, and insufficient efficacy against resistant bacterial strains. Despite this, the structural and mechanistic knowledge embedded in these failed molecules constitutes a largely underutilized resource for medicinal chemistry. With antimicrobial resistance now recognized as one of the most serious global health threats, understanding why these compounds failed is not only a retrospective exercise but also a strategic priority for the rational design of next-generation antibiotics.This Research Topic aims to critically examine antibiotics that advanced to clinical trials but did not receive FDA approval, with the goal of extracting practical lessons from their structural, pharmacological, and chemical failures. Adopting a synthetic chemistry perspective, this collection will systematically analyze the molecular determinants of pipeline attrition, from problems with target selectivity and resistance acquisition to pharmacokinetic liabilities and manufacturability constraints. The main objective is to translate these lessons into rational strategies for the design of novel antimicrobial scaffolds capable of overcoming the documented limitations of their predecessors. In doing so, this Research Topic bridges medicinal chemistry, pharmacology, and infectious disease medicine, supporting a data-driven approach to antibiotic discovery at a time when new therapeutic options are urgently needed.We welcome original research articles, systematic reviews and perspectives addressing the chemical and pharmacological analysis of antibiotic candidates that failed to reach FDA approval. Specific themes of interest include structure-activity relationship (SAR) analyses of failed clinical compounds; synthetic chemistry strategies to overcome documented molecular liabilities; mechanisms of target engagement failure; chemical modifications addressing pharmacokinetic shortcomings; computational and AI-assisted approaches to scaffold optimization; and case studies on individual compounds or antibiotic classes that failed late-stage development. Contributions examining novel molecular scaffolds rationally designed from failed predecessors are particularly encouraged. Studies spanning all major bacterial targets, including cell wall biosynthesis, DNA replication, protein synthesis, and membrane integrity, are within scope. Topic editors: Maytham Hussein, Dr. Santosh L. Gaonkar, FRSC, Miguel Garcia Castro Source: https://www.frontiersin.org/research-topics/82949/antibiotic-pipeline-attrition-rational-design-strategies-inspired-by-clinical-candidates-that-failed-to-reach-fda-approval