Understanding the catalytic mechanism of β-lactam antibiotic breakdown by class A β-lactamases through QM/MM MD simulations Hira Jabeen 1 , Michael Beer 2 , James Spencer ,2 , Marc W. van der Kamp ,2,4 , H. Adrian Bunzel 1,3 , Adrian J. Mulholland 1 1 Centre for Computational Chemistry, School of Chemistry, University of Bristol, UK, 2 School of Cellular and Molecular Medicine, University of Bristol, UK, 3 Department of Biosystem Science and Engineering, ETH Zurich, CH, 4 School of Biochemistry, University of Bristol, UK Antimicrobial resistance (AMR) refers to the ability of microorganisms to survive and remain viable in the presence of antibiotics, disinfectants, and food preservatives that eradicate bacteria, parasites, viruses, and fungi. AMR is an alarming concern of the 21 st century, exacerbated by excessive use of antibiotics jeopardizing the efficacy of life-saving drugs worldwide. Antibiotics have revolutionized medicine and saved countless lives but are threatened by bacterial resistance with serious implications for public health, medical treatment, and global economies. According to the World Health Organization, it is associated with 4.95 million deaths in 2019 and 1.27 million directly caused by AMR. Tackling AMR by appropriate use of antimicrobials in humans and animals is one of the major goals of the sustainable development goals (SDGs). The relationship between humans, animals, plants, food safety, and the environmental sector is increasingly recognized in the context of the evolution of AMR. In order to effectively tackle AMR, it is crucial to adopt a “One Health” approach that is aligned with the principles of SDGs that aim to address global challenges 1 . Combating this crisis is hindered by a limited understanding of the catalytic drivers in emerging resistance-mediating enzymes such as β-lactamases. AMR mediated by β-lactamases threatens carbapenems, the ‘last resort’ antibiotics for treating several bacterial infections. Carbapenem hydrolysis by class A β-lactamases causes clinically relevant resistance and is of particular concern. While older prevalent class A β-lactamases are inhibited by carbapenems, the newly evolved enzymes capable of breaking down carbapenems are becoming increasingly widespread. Here we used QM/MM MD calculations to investigate the breakdown of carbapenem by ten class A β-lactamases. After reproducing their experimentally observed reaction barriers of the rate-limiting deacylation reaction 2 , we assessed how their electrostatic interactions contribute to activity by calculating active-site electric fields. The electric fields correlate well with activity, with contributions from a cluster of seven residues distinguishing resistance-mediating enzymes. The electric field analysis provides insights into the molecular determinants of activity with understanding the evolution of antibiotic resistance and may guide the design of next-generation antibiotics. References 1. World Health, O.; Food; Agriculture Organization of the United, N.; World Organisation for Animal, H., Antimicrobial resistance and the United Nations sustainable development cooperation framework: guidance for United Nations country teams . World Health Organization: Geneva, 2021. 2. Chudyk, E. I.; Limb, M. A. L.; Jones, C.; Spencer, J.; van der Kamp, M. W.; Mulholland, A. J., QM/MM simulations as an assay for carbapenemase activity in class A β-lactamases. Chemical Communications 2014, 50 (94), 14736-14739.
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