We present both experimental and theoretical results on simple model systems of zinc-β-lactamases. Kinetic studies show that the rate of degradation of β-lactam antibiotics in the presence of zinc ions and tris(hydroxymethyl)aminomethane buffers depends markedly on the structure of the β-lactam. Carbapenems are highly reactive whereas monobactam antibiotics like aztreonam, which are known to be non-susceptible to the catalytic action of the metallo-β-lactamases, are less reactive by three orders of magnitude. To complement the experimental studies, density functional calculations were carried out on model systems. These calculations allowed us to characterise the reactive mode of binding between the β-lactam nucleus and Zn²⁺ ions as well as to rationalise the kinetic trends observed experimentally. Docking analyses are reported for the complex formed between aztreonam and the mononuclear metallo-β-lactamase from Bacillus cereus. On the basis of all the results, we hypothesise that the aztreonam–metallo-β-lactamase complex might be poorly reactive due to a potential interaction of the N-sulfonate group of aztreonam with the essential Zn ion at the active site.