The article provides an academic perspective on the drug discovery efforts in the field of β-lactams, focusing on the challenges and advancements in combating antibiotic resistance. β-Lactams are widely used antibiotics that inhibit penicillin-binding proteins (PBPs) and transpeptidases, which are crucial for peptidoglycan synthesis in bacterial cell walls. The primary mechanism of antibiotic resistance involves the production of β-lactamase enzymes, which hydrolyze β-lactam antibiotics. To counter this resistance, researchers have focused on three main areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. The article highlights recent findings on both β-lactamases and cell wall transpeptidases, emphasizing their evolutionary and functional connections. It discusses the development of new β-lactams that target both transpeptidases and β-lactamases, as well as the progress in understanding the targets, screening methodologies, and new inhibitor chemotypes. Cyclic boronate compounds and diazabicyclooctane (DBO) series of small molecules have shown promise in inhibiting β-lactamases and potentially targeting PBPs directly. The article also reviews the challenges and opportunities in drug discovery, including the need for novel inhibitor chemotypes to counter future resistance. It covers the structural and functional similarities between β-lactamases and PBPs, and the use of computational methods and experimental techniques to identify and optimize inhibitors. The article concludes by discussing the potential of dual-action inhibitors that target both β-lactamases and PBPs, as well as the development of new β-lactams and non-β-lactam scaffolds for cell wall transpeptidase inhibition.The article provides an academic perspective on the drug discovery efforts in the field of β-lactams, focusing on the challenges and advancements in combating antibiotic resistance. β-Lactams are widely used antibiotics that inhibit penicillin-binding proteins (PBPs) and transpeptidases, which are crucial for peptidoglycan synthesis in bacterial cell walls. The primary mechanism of antibiotic resistance involves the production of β-lactamase enzymes, which hydrolyze β-lactam antibiotics. To counter this resistance, researchers have focused on three main areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. The article highlights recent findings on both β-lactamases and cell wall transpeptidases, emphasizing their evolutionary and functional connections. It discusses the development of new β-lactams that target both transpeptidases and β-lactamases, as well as the progress in understanding the targets, screening methodologies, and new inhibitor chemotypes. Cyclic boronate compounds and diazabicyclooctane (DBO) series of small molecules have shown promise in inhibiting β-lactamases and potentially targeting PBPs directly. The article also reviews the challenges and opportunities in drug discovery, including the need for novel inhibitor chemotypes to counter future resistance. It covers the structural and functional similarities between β-lactamases and PBPs, and the use of computational methods and experimental techniques to identify and optimize inhibitors. The article concludes by discussing the potential of dual-action inhibitors that target both β-lactamases and PBPs, as well as the development of new β-lactams and non-β-lactam scaffolds for cell wall transpeptidase inhibition.