Browse/search for people

Publication - Professor Adrian Mulholland

    Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

    Citation

    Fritz, R, Alzate-Morales, JH, Spencer, J, Mulholland, AJ & Van Der Kamp, MW, 2018, ‘Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition’. Biochemistry.

    Abstract

    Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.

    Full details in the University publications repository