Metallo-β-lactamases (MβLs) constitute an increasingly serious clinical threat by giving rise to β-lactam antibiotic resistance. They accommodate in their catalytic pocket one or two zinc ions, which are responsible for the hydrolysis of β-lactams. Recent x-ray studies on a member of the mono-zinc B2 MβLs, CphA from Aeromonas hydrophila, have paved the way to mechanistic studies of this important subclass, which is selective for carbapenems. Here we have used hybrid quantum mechanical/ molecular mechanical methods to investigate the enzymatic hydrolysis by CphA of the antibiotic biapenem. Our calculations describe the entire reaction and point to a new mechanistic description, which is in agreement with the available experimental evidence. Within our proposal, the zinc ion properly orients the antibiotic while directly activating a second catalytic water molecule for the completion of the hydrolytic cycle. This mechanism provides an explanation for a variety of mutagenesis experiments and points to common functional facets across B2 and B1 MβLs