Structure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome β-Lactam Resistance in Staphylococcus aureus (MRSA)

Abstract

β-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering β-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low β-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing β-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens.

Crystal Structures of Penicillin-Binding Protein 3 (PBP3) from Methicillin-Resistant Staphylococcus aureus in the Apo and Cefotaxime‐Bound Forms

“…(In the case of the class A enzyme S. pneumoniae PBP1b, it was necessary to use an Asn-to-Gly mutant to open up the active site and facilitate inhibitor soaking. 36 ) Most of the residues in the immediate vicinity of any bound inhibitor are conserved between PBP2, SA-PBP2a, and SA-PBP3. However, even though Tyr446 of PBP2a interacts with the aromatic ring of bound methicillin, 24 the equivalent residue of PBP3, Tyr430, points away from the active site and sits between Phe341 and His447.…”

Resistance to antibiotics targeted to the bacterial cell wall

“…The development of non‐β‐lactam inhibitors of PBPs has been a strategy of choice, with the goal of circumventing (at least temporarily) the resistance process. A number of molecules have been developed, notably lactivicins, rhodanines, quinolones, and boronates . Of these, lactivicins and boronates have been shown to be able to not only inhibit specific PBPs but also eliminate drug‐resistant bacteria .…”

Synthesis, biological evaluation, quantitative-SAR and docking studies of novel chalcone derivatives as antibacterial and antioxidant agents

“…IIIc, IIIf, IIIg). Therefore, to predict the possible mechanism by which the chalcone derivatives can induce antibacterial activity, molecular docking of the potent antibacterial compound IIIf was performed on the binding model based on PBP-1b of S. aureus (2Y2H.pdb) and the docking result of IIIf was compared with the interaction of N-alkyl boronic acid analogues, the PBP1b inhibitors of S. aureus (Contreras-Martel et al, 2011). The docking results show (Fig.…”