For Penicillin Binding Proteins, why is the enzyme-peptide complex less stable than the enzyme-β-lactam complex?
According to Foyes Principle of Medicinal Chemistry, the significant difference is the crowding of the active site by the cycle next to the lactam ring, which prevent attack on the ester and release of the drug from the PBP.



Reversing the reaction to the beta-lactam is unfavorable given the resulting ring strain.

I would personally expect the ester to be hydrolysable (water being much smaller), but not very rapidly given the active site somewhat shields the complex from water. Foyes disagrees on that. ("Water is also an insufficiently effective nucleophile and cannot hydrolyze the complex either.")