Structural Insights into the Anti-methicillin-resistant Staphylococcus aureus (MRSA) Activity of Ceftobiprole

One ring to rule them all: Current trends in combating bacterial resistance to the β‐lactams

“…3(C)]. 59 Furthermore, a similar displacement of the b3 strand and the N-terminal portion of the a2 helix are observed in the ceftobiprole bound structure as was seen previously in other b-lactam bound PBP2a acyl-enzyme complexes [ Fig. 3(D)].…”

“…Both conformations of the oxyimino aminothiadiazolyl side chain had been previously observed in studies involving the similar R1 group of cefotaxime, but never before in the same structure. 59 The observed conformational variability likely presents an entropic gain for the bound ceftobiprole, a common affect observed for ligands that bind in multiple conformations. 60 Importantly, the ceftobiprole R2 group is sandwiched in a hydrophobic pocket adjacent to the active site, and the R2 pyrrolidine rings form favorable pi-pi interactions with M641, T600, and Y446 [ Fig.…”

“…Furthermore, the non-specific hydrophobic nature of its interactions within the active site may permit the conformational plasticity required to facilitate the necessary rearrangements during acylation. 59 Anti-MRSA b-lactams are typically cephalosporins like ceftobiprole, an observation that is thought to be due to increased van der Waals contacts with the R2 of cephalosporins, a functionality that is absent in other b-lactam classes. 61 The motif iii residue T600…”

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

“…Ceftaroline inhibits PBP 2a allosterically by binding to the protein and causing a conformational change, which makes PBP 2a vulnerable to the action of a second molecule of ceftaroline or another ␤-lactam (20). Ceftobiprole bypasses the resistance mechanism of PBP 2a by having a vinylpyrrolidinone moiety (R2 group) that allows access to the PBP 2a active site (20,21). MRSA strains that are resistant to ceftaroline and ceftobiprole have already been reported (13,(22)(23)(24)(25).…”

Ceftobiprole- and Ceftaroline-Resistant Methicillin-Resistant Staphylococcus aureus

“…Ceftobiprole and ceftaroline are anti-MRSA cephalosporins that inhibit PBP2a at therapeutically useful concentrations. The R2 group of ceftobiprole extends into the narrow cleft of PBP2a to access the active site, whereas ceftaroline binding causes an allosteric change in PBP2a, revealing the active site for binding by a second molecule (3,4). Ceftobiprole has been evaluated in clinical trials, and ceftaroline is FDA approved for treat-ment of skin and skin structure infections, including those caused by MRSA (5)(6)(7)(8)(9)(10).…”