Synthetic Innovation in Antibiotic Structural Modification: Novel Methodologies for Overcoming Resistance

The global antimicrobial resistance (AMR) crisis has rendered many conventional antibiotics ineffective, with the WHO designating AMR as one of the top ten global public health threats. Unlike efforts centered on retrospective analysis of failed clinical candidates or on combination-therapy and dosing optimization, this Research Topic focuses on de novo synthetic innovation in antibiotic scaffold design. Structure-activity relationship (SAR) studies remain fundamental to rational antibiotic design, enabling systematic modification of chemical scaffolds to elucidate structural determinants of antibacterial potency, selectivity, and safety. Recent advances in synthetic methodologies — including peptide-catalyzed modifications, combinatorial biosynthesis, and genome mining-guided diversification — have expanded the chemical space accessible for antibiotic optimization, particularly for natural product-derived scaffolds. Multi-dimensional bioactivity evaluation frameworks integrating in vitro susceptibility testing, resistance frequency studies, pharmacokinetic/pharmacodynamic (PK/PD) profiling, and toxicity assessment are essential for translating structural modifications into clinically viable candidates.Despite extensive structure-activity relationship (SAR) investigations across major antibiotic classes — including β-lactams, macrolides, fluoroquinolones, glycopeptides, and pleuromutilins — the emergence of multidrug-resistant ESKAPE pathogens continues to outpace the development of novel therapeutics. This Research Topic aims to bridge the critical gap between structural modification and comprehensive bioactivity validation by fostering interdisciplinary collaboration among medicinal chemists, microbiologists, pharmacologists, and computational scientists. We seek to advance synthetic strategies that yield scaffolds structurally and sterically incompatible with established resistance pathways, while simultaneously optimizing pharmacological properties. Recent advances in artificial intelligence-driven drug design, molecular dynamics simulations, and high-throughput screening platforms offer unprecedented opportunities to accelerate lead optimization. By integrating computational predictions with rigorous experimental validation, this collection will contribute to the global pipeline of next-generation antimicrobials capable of combating recalcitrant infections.This Research Topic welcomes Original Research, Review, Mini-Review, Perspective, and Brief Research Report manuscripts addressing:Synthetic innovation in structural modification of existing antibiotic scaffolds, particularly natural product-derived compounds, to circumvent resistanceNovel synthetic methodologies — including peptide-catalyzed modifications, combinatorial biosynthesis, and genome mining — for site-selective derivatizationSAR/QSAR studies integrating molecular docking, machine learning, and molecular dynamics simulationsMulti-dimensional bioactivity evaluation encompassing MIC/MBC determination, time-kill kinetics, resistance frequency studies, in vivo efficacy models, and PK/PD profilingAntibiotic hybrids and dual-acting conjugates targeting multiple bacterial pathwaysMechanistic studies on how structural alterations influence target binding, membrane penetration, and resistance evasionContributions bridging medicinal chemistry with advanced bioassays, as well as those exploring AI-assisted design strategies, are particularly encouraged. In line with our editorial policies, manuscripts primarily comprising bioinformatics analyses, molecular docking and structure predictions, molecular dynamics simulations, or other computational studies (including those involving AI) must include or refer to appropriate biological validation, in vitro and/or in vivo. Topic editors: Yunpeng Yi, Ning Ma, Chandra S Verma Source: https://www.frontiersin.org/research-topics/84382/synthetic-innovation-in-antibiotic-structural-modification-novel-methodologies-for-overcoming-resistance