2Y2L

PENICILLIN-BINDING PROTEIN 1B (PBP-1B) IN COMPLEX WITH AN ALKYL BORONATE (E06)

Summary for 2Y2L

• Entry DOI: 10.2210/pdb2y2l/pdb
• Related: 2UWX 2XD1 2XD5 2Y2G 2Y2H 2Y2I 2Y2J 2Y2K 2Y2M 2Y2N 2Y2O 2Y2P 2Y2Q
• Descriptor: PENICILLIN-BINDING PROTEIN 1B, [(1R)-1-[(2,6-difluorophenyl)carbonylamino]ethyl]-trihydroxy-boron, SULFATE ION, ... (6 entities in total)
• Functional Keywords: transferase, infection, cell wall, peptidoglycan, inhibitor
• Biological source: STREPTOCOCCUS PNEUMONIAE
• Total number of polymer chains: 2
• Total formula weight: 110093.86

Authors

Contreras-Martel, C.,Amoroso, A.,Woon, E.C.,Zervosen, A.,Inglis, S.,Martins, A.,Verlaine, O.,Rydzik, A.,Job, V.,Luxen, A.,Joris, B.,Schofield, C.J.,Dessen, A. (deposition date: 2010-12-15, release date: 2011-08-03, Last modification date: 2024-11-13)

Primary citation

Contreras-Martel, C.,Amoroso, A.,Woon, E.C.,Zervosen, A.,Inglis, S.,Martins, A.,Verlaine, O.,Rydzik, A.,Job, V.,Luxen, A.,Joris, B.,Schofield, C.J.,Dessen, A.
Structure-Guided Design of Cell Wall Biosynthesis Inhibitors that Overcome Beta-Lactam Resistance in Staphylococcus Aureus (Mrsa).
Acs Chem.Biol., 6:943-, 2011

PubMed 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.

PubMed: 21732689
DOI: 10.1021/CB2001846

Experimental method

X-RAY DIFFRACTION (2.07 Å)