Neutral β-Lactams Inactivate High Molecular Mass Penicillin-Binding Proteins of Class B1, Including PBP2a of MRSA

Abstract

The targets of β-lactam antibiotics are bacterial DD-peptidases (penicillin-binding proteins). β-Lactam SAR studies over many years have demonstrated the importance of a specifically placed negative charge, usually carboxylate, on these molecules. We show here that neutral analogues of classical β-lactam antibiotics are of comparable activity to the originals against β-lactam-resistant high molecular mass DDpeptidases of the B1 class, a group that includes PBP2a of methicillin-resistant Staphylococcus aureus. These neutral β-lactams may direct new development of antibiotics against certain penicillin-resistant bacteria. These molecules do have antibiotic activity against Gram-positive bacteria.

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

“…This being the case, then new antimicrobials directed against resistant strains should avoid inclusion of a carboxylate or equivalent. It is interesting to note that neutral ␤-lactams lacking the carboxylate inhibit PBP3 from Bacillus subtilis and PBP2a from S. aureus at a similar level of activity to the same ␤-lactams containing a carboxylate (48). By not relying on ␤3 rotation for activity, such compounds may offer a means to circumvent this type of resistance mechanism.…”

High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes

“…The direct hydrogen-bonds to Gly534 and Gly535 are unusual for PBP3 inhibitors that occupy the carboxylic acid binding pocket, that is, the pocket binding the C-3 penicillin carboxylate (Figure S5). These structures therefore provide support for the future design of PBP3 inhibitors incorporating either weakly acidic non-carboxylates or neutral groups that interact with the “acid binding pocket” of PBP3, which is typically occupied by the C-3 carboxylate of β-lactams (penicillin nomenclature) (Figure S5).…”

The Tipper–Strominger Hypothesis and Triggering of Allostery in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus (MRSA)

“…The findings presented here emerged from the discovery of allosteric regulation of PBP2a in MRSA. The triggering of allostery by ceftaroline sheds light on the prospect of both nontraditional structure–activity development for β-lactams targeting PBPs subject to allosteric control and to non-β-lactam compounds that could bind to the allosteric site and elicit the same potentiation of β-lactam efficacy against MRSA infection. There is considerable interest in potentiators of antibiotics, in light of the profound clinical problems with resistance. ,− Our studies also indicate that binding to the acyl- d -Ala- d -Ala terminus of the pentapeptide of the nascent peptidoglycan has driven not only evolution of the transpeptidase active site for its substrate, but also that of the allosteric site.…”

“…The findings presented here emerged from the discovery of allosteric regulation of PBP2a in MRSA. The triggering of allostery by ceftaroline sheds light on the prospect of both nontraditional structure−activity development for β-lactams targeting PBPs subject to allosteric control 38 and to non-βlactam compounds that could bind to the allosteric site and elicit the same potentiation of β-lactam efficacy against MRSA infection. There is considerable interest in potentiators of antibiotics, in light of the profound clinical problems with resistance.…”