1 research outputs found
The Tipper–Strominger Hypothesis and Triggering of Allostery in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus (MRSA)
The
transpeptidases involved in the synthesis of the bacterial
cell wall (also known as penicillin-binding proteins, PBPs) have evolved
to bind the acyl-d-Ala-d-Ala segment of the stem
peptide of the nascent peptidoglycan for the physiologically important
cross-linking of the cell wall. The Tipper–Strominger hypothesis
stipulates that β-lactam antibiotics mimic the acyl-d-Ala-d-Ala moiety of the stem and, thus, are recognized
by the PBPs with bactericidal consequences. We document that this
mimicry exists also at the allosteric site of PBP2a of methicillin-resistant Staphylococcus aureus (MRSA). Interactions of different
classes of β-lactam antibiotics, as mimics of the acyl-d-Ala-d-Ala moiety at the allosteric site, lead to a conformational
change, across a distance of 60 Ă… to the active site. We directly
visualize this change using an environmentally sensitive fluorescent
probe affixed to the protein loops that frame the active site. This
conformational mobility, documented in real time, allows antibiotic
access to the active site of PBP2a. Furthermore, we document that
this allosteric trigger enables synergy between two different β-lactam
antibiotics, wherein occupancy at the allosteric site by one facilitates
occupancy by a second at the transpeptidase catalytic site, thus lowering
the minimal-inhibitory concentration. This synergy has important implications
for the mitigation of facile emergence of resistance to these antibiotics
by MRSA