Abstract
The crystal structure of the class D β-lactamase OXA-436 was solved to a resolution of 1.80 Å. Higher catalytic rates were found at higher temperatures for the clinically important antibiotic imipenem, indicating better adaptation of OXA-436 to its mesophilic host than OXA-48, which is believed to originate from an environmental source. Furthermore, based on the most populated conformations during 100 ns molecular-dynamics simulations, it is postulated that the modulation of activity involves conformational shifts of the α3-α4 and β5-β6 loops. While these changes overall do not cause clinically significant shifts in the resistance profile, they show that antibiotic-resistance enzymes exist in a continuum. It is believed that these seemingly neutral differences in the sequence exist on a path leading to significant changes in substrate selectivity.
Highlights
Carbapenemases are enzymes that hydrolyze the carbapenem class of -lactam antibiotics, rendering the antibiotics ineffective against bacteria that carry carbapenemase genes (Bush & Bradford, 2016)
The observed melting point indicates that OXA-436 is less thermostable than OXA-48, which has a melting temperature of 55.2C, but the melting point is in the observed range for other OXA-48-like enzymes (Lund et al, 2017), and considering the mesophilic environment for the bacterial origin of OXA-436 this is unlikely to be a functional problem
The carbapenem-hydrolyzing class D -lactamase OXA-436 has been characterized as a mesophilic variant of OXA-48, Figure 6 Arrhenius plot of OXA-48 and OXA-436 with the carbapenem substrate imipenem
Summary
Carbapenemases are enzymes that hydrolyze the carbapenem class of -lactam antibiotics, rendering the antibiotics ineffective against bacteria that carry carbapenemase genes (Bush & Bradford, 2016). It is worrying when carbapenemase genes are detected in pathogenic bacteria belonging to the Enterobacteriaceae family, such as Klebsiella pneumoniae. We have previously described the dissemination of the carbapenemase oxacillinase-436 (OXA-436) in pathogenic strains from multiple Danish hospitals and have shown that the enzyme is a class D carbapenemase (Samuelsen et al, 2018) similar to OXA-48 in terms of substrate specificity. It would be of interest to identify structural features that functionally differentiate the OXA-48-like enzymes.
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