scaffold for new antibacterial agents and combines two complementary strategies: the development of monobactam inhibitors of bacterial transpeptidases with antibacterial activity, and the computational discovery of metallo-β-lactamase inhibitors. A modular monocyclic β-lactam synthon allowing late-stage derivatization at the N1, C3 and C4 positions was developed and used to prepare derivatised compounds, although the lengthy synthesis makes the preparation of large libraries impractical. Starting from a crystal structure of aztreonam, structure-based design yielded new penicillin-binding-protein inhibitors, the most potent forming a halogen bond with a conserved threonine, and crystal structures revealed that the ATMO side chain points towards solvent and tolerates conjugation. Exploiting this, five conjugate series were prepared from aztreonam, combining transpeptidase inhibition with additional mechanisms: nitroxides, acyl homoserine lactones, guanidines and biguanides, permanently charged groups, and dual inhibitors targeting both D,D- and L,D-transpeptidases. These compounds inhibited transpeptidases and showed antibacterial activity. The guanidine series was most promising, improving activity against difficult pathogens and markedly slowing resistance development. Outer-membrane permeability and efflux were consistently identified as the main limitations. Finally, repurposing a chloroacetamide library as mercaptoacetamides yielded NDM-1 inhibitors, and a crystal structure guided virtual screening that delivered further micromolar inhibitors with diverse zinc-binding groups. Overall, the work delivers new synthetic routes, structural insights into monobactam–PBP interactions, and several inhibitor series, contributing new approaches to the development of monobactam antibacterials and metallo-β-lactamase inhibitors against antimicrobial resistance.
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