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PresentationsMechanism of inhibition of penicillin-binding protein 3 from Pseudomonas aeruginosa by (2-nitrobenzamido)methylboric acidLomonosov Moscow State University, Faculty of Chemistry, Department of Physical Chemistry, Russia, 119234, Moscow, Leninskie Gory 1, Phone: (495)939-20-35, E-mail: mkhrenova@lcc.chem.msu.ru 1N.M. Emanuel Institute of Biochemical Physics RAS, Russia, 119334, Moscow, st. Kosygina 4 2Research Center of Biotechnology RAS, Russia, 119071, Moscow, Leninsky Prospekt 33/2 Pseudomonas aeruginosa is a pathogenic microorganism for humans, causing nosocomial infections. The treatment of ones is limited due to the bacterium resistance to antibiotics. Penicillin-binding protein 3 (PBP3) is an important enzyme responsible for the last stages of peptide glycan synthesis in the bacterial cell wall. Inactivation of PBP3 by β lactam antibiotics makes it a key therapeutic target [1]. The effectiveness of β-lactam antibiotics is sharply reduced, mainly due to bacterial β-lactamase enzymes. Boron-based inhibitors are promising inhibitors of PBP and serine-β-lactamases. Boron-based inhibitors can exploit the Lewis acidity of the boron atom to engage in specific interactions with the nucleophilic serine in the active site of the enzyme. Nevertheless, the interaction between boron-based compounds and PBP is currently unstudied. It was shown that unusual tricovalent adducts are formed in reaction between PBP and boron-containing inhibitors [2, 3]. The possibility of forming highly coordinated complexes may lead to the creation of more effective inhibitors. In this research, molecular modeling of the reaction mechanism of inhibition of PBP3 from Pseudomonas aeruginosa by (2-nitrobenzamido)methylboronic acid was performed. The PBP3-inhibitor complex was established by the molecular dynamics approach and the Gibbs energy profiles of reaction mechanism were determined by the molecular dynamics method with QM/MM potentials.
References 1. Glen K. A., Lamont I. L. Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division. J. Antimicrob. Chemother., 2024. 2170-2178 P. 2. Zervosen A., Herman R., Kerff F., et al. Unexpected tricovalent binding mode of boronic acids within the active site of a penicillin-binding protein. J. Am. Chem. Soc., 2011. 10839-10848 P. 3. Newman H., Krajnc A., Bellini D., et al. High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes. J. Med. Chem., 2021. 11379-11394 P.
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