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Structural and biochemical characterization of the environmental MBLs MYO-1, ECV-1 and SHD-1.

Artikel i vetenskaplig tidskrift
Författare Christopher Fröhlich
Vidar Sørum
Sandra Huber
Ørjan Samuelsen
Fanny Berglund
Erik Kristiansson
Stathis Kotsakis
Nachiket Marathe
D. G. Joakim Larsson
Hanna-Kirsti S Leiros
Publicerad i The Journal of antimicrobial chemotherapy
ISSN 1460-2091
Publiceringsår 2020
Publicerad vid Institutionen för matematiska vetenskaper
CARe - Centrum för antibiotikaresistensforskning
Institutionen för biomedicin, avdelningen för infektionssjukdomar
Språk en
Länkar dx.doi.org/10.1093/jac/dkaa175
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord antibiotics
Ämneskategorier Mikrobiologi inom det medicinska området, Bioinformatik och systembiologi, Mikrobiologi, Biokemi och molekylärbiologi

Sammanfattning

MBLs form a large and heterogeneous group of bacterial enzymes conferring resistance to β-lactam antibiotics, including carbapenems. A large environmental reservoir of MBLs has been identified, which can act as a source for transfer into human pathogens. Therefore, structural investigation of environmental and clinically rare MBLs can give new insights into structure-activity relationships to explore the role of catalytic and second shell residues, which are under selective pressure.To investigate the structure and activity of the environmental subclass B1 MBLs MYO-1, SHD-1 and ECV-1.The respective genes of these MBLs were cloned into vectors and expressed in Escherichia coli. Purified enzymes were characterized with respect to their catalytic efficiency (kcat/Km). The enzymatic activities and MICs were determined for a panel of different β-lactams, including penicillins, cephalosporins and carbapenems. Thermostability was measured and structures were solved using X-ray crystallography (MYO-1 and ECV-1) or generated by homology modelling (SHD-1).Expression of the environmental MBLs in E. coli resulted in the characteristic MBL profile, not affecting aztreonam susceptibility and decreasing susceptibility to carbapenems, cephalosporins and penicillins. The purified enzymes showed variable catalytic activity in the order of <5% to ∼70% compared with the clinically widespread NDM-1. The thermostability of ECV-1 and SHD-1 was up to 8°C higher than that of MYO-1 and NDM-1. Using solved structures and molecular modelling, we identified differences in their second shell composition, possibly responsible for their relatively low hydrolytic activity.These results show the importance of environmental species acting as reservoirs for MBL-encoding genes.

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