The article discusses the increasing prevalence of antibiotic-resistant pathogens and the need for new antibiotics to combat these threats. It highlights the historical reliance on a small set of molecular scaffolds for antibiotic development, which has led to the slow progress in discovering new antibiotics. The authors argue that the discovery of new scaffolds should be a priority, as the emergence of multidrug resistance among pathogens suggests that the functional lifetimes of existing scaffolds are limited. The article outlines several promising approaches to scaffold discovery, including mining underexplored microbial niches for natural products, designing screens that avoid rediscovering old scaffolds, and repurposing libraries of synthetic molecules. It also emphasizes the importance of natural products, particularly from marine and terrestrial symbioses, and the use of bioinformatics to identify new targets and scaffolds. The authors discuss the challenges and limitations of synthetic molecule discovery, such as the failure of bacterial genomics to validate novel targets or yield new antibiotics. They suggest that repurposing external compound libraries and using unbiased whole-cell screens can help overcome these challenges. Additionally, they propose a more inclusive approach to target selection, grouping targets by common inhibitor scaffolds rather than pathways. Finally, the article explores the potential of narrow-spectrum antibiotics and combination therapies, noting that while broad-spectrum antibiotics are ideal, the need for more specific agents may lead to the development of genus-selective antibiotics. The authors conclude that new scaffolds, whether natural or synthetic, broad-spectrum or narrow, will be essential for combating antibiotic resistance.The article discusses the increasing prevalence of antibiotic-resistant pathogens and the need for new antibiotics to combat these threats. It highlights the historical reliance on a small set of molecular scaffolds for antibiotic development, which has led to the slow progress in discovering new antibiotics. The authors argue that the discovery of new scaffolds should be a priority, as the emergence of multidrug resistance among pathogens suggests that the functional lifetimes of existing scaffolds are limited. The article outlines several promising approaches to scaffold discovery, including mining underexplored microbial niches for natural products, designing screens that avoid rediscovering old scaffolds, and repurposing libraries of synthetic molecules. It also emphasizes the importance of natural products, particularly from marine and terrestrial symbioses, and the use of bioinformatics to identify new targets and scaffolds. The authors discuss the challenges and limitations of synthetic molecule discovery, such as the failure of bacterial genomics to validate novel targets or yield new antibiotics. They suggest that repurposing external compound libraries and using unbiased whole-cell screens can help overcome these challenges. Additionally, they propose a more inclusive approach to target selection, grouping targets by common inhibitor scaffolds rather than pathways. Finally, the article explores the potential of narrow-spectrum antibiotics and combination therapies, noting that while broad-spectrum antibiotics are ideal, the need for more specific agents may lead to the development of genus-selective antibiotics. The authors conclude that new scaffolds, whether natural or synthetic, broad-spectrum or narrow, will be essential for combating antibiotic resistance.