Discovery, Synthesis and Design of the Novel Antibacterial Agents

Antimicrobial resistance (AMR) has emerged as one of the most pressing global health challenges of the 21st century, with the World Health Organization warning that drug-resistant infections could claim 10 million lives annually by 2050 if left unchecked. The clinical pipeline for novel antibacterial agents remains alarmingly thin, particularly for Gram-negative pathogens and multidrug-resistant tuberculosis, where existing therapeutic options are rapidly dwindling. Traditional discovery platforms have yielded limited returns, necessitating a paradigm shift toward mechanism-guided molecular design, natural product engineering, and artificial intelligence-assisted compound generation. Meanwhile, structural biology advances and high-throughput screening technologies have opened new avenues for targeting bacterial ribosomes, cell membranes, and metabolic pathways with unprecedented precision. This Research Topic seeks to capture these converging innovations, providing a timely forum for chemists, computational biologists, and microbiologists to share breakthroughs in antibacterial agent discovery and optimization.The central problem addressed by this Research Topic is the critical shortage of mechanistically novel antibacterial agents capable of overcoming clinically relevant resistance mechanisms. Despite decades of antibiotic development, the discovery pipeline has been dominated by analogs of existing scaffolds, leaving pathogens with efflux pumps, target modification, and biofilm-mediated resistance largely unchallenged. To break this impasse, this collection aims to bridge three converging advances: (i) structure-enabled rational design leveraging cryo-EM-resolved ribosome complexes and AI-driven molecular generation platforms such as diffusion models and reinforcement learning for de novo lead optimization; (ii) synthetic methodology innovation enabling late-stage functionalization of natural product scaffolds—notably pleuromutilins, tetracyclines, and macrolides—to evade established resistance determinants; and (iii) integrated in silico–in vitro workflows combining molecular dynamics simulations, ADMET prediction, and high-content screening to accelerate hit-to-lead translation. By uniting contributions from medicinal chemistry, computational biology, and microbiology, this Special Issue seeks to establish actionable strategies for targeting priority pathogens identified by WHO, ultimately advancing preclinical candidates with defined mechanisms and favorable resistance profiles toward clinical evaluation.This Research Topic welcomes contributions addressing the discovery, design, and synthesis of novel antibacterial agents with activity against multidrug-resistant pathogens. Specific themes include: • structure-based and fragment-based design of ribosome-targeting antibiotics (e.g., pleuromutilins, macrolides, oxazolidinones); • AI-driven molecular generation and deep learning-assisted SAR optimization; • natural product derivatization and biosynthetic pathway engineering; • novel targets in bacterial cell wall, membrane, and metabolism; • resistance mechanism-guided scaffold hopping and evasion strategies; • integrated computational–experimental workflows combining molecular dynamics, docking, and phenotypic screening. We are interested in Original Research articles, Reviews, and Mini-Reviews presenting robust chemical, biological, or computational data. Manuscripts reporting single-target activity without mechanistic insight or structural information will be considered out of scope. All submissions must demonstrate novelty in chemical structure, target engagement, or methodological approach, with clear implications for combating antimicrobial resistance. Topic editors: Yunpeng Yi, Zhihai Liu, Shuqian Lin Source: https://www.frontiersin.org/research-topics/85667/discovery-synthesis-and-design-of-the-novel-antibacterial-agents