For Penicillin Binding Proteins, why is the enzyme-peptide complex less stable than the enzyme-β-lactam complex?

Question

I'm trying to figure this out. I cannot find any publications that go into good detail about the chemistry of PBP inhibition by β-lactam antibiotics.

PBPs cross-link adjacent pentapeptides to form peptidoglycan. My understanding is that, in most bacteria, this pentapeptide has a terminal D-Ala-D-Ala dipeptide. The enzyme removes the terminal D-Ala and forms a D-Ala-Enzyme complex, where the enzyme is linked to the rest of the peptide via ester bond to the D-Ala.

However, when PBPs bind to β-lactams, they also form a β-lactam-ester-enzyme complex. However, this complex is more stable so the β-lactam remains in the active site. Why?

Any good publications are also very welcome.

I would also like to ask, is there any reason the "β-lactamoyl-enzyme" complex can't be hydrolysed?

Answer 1

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.")