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Article

Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem

1
Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA
2
Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
3
Research Service, Louis Stokes Cleveland VAMC, 10701 East Blvd 151W, Cleveland, OH 44106, USA
*
Authors to whom correspondence should be addressed.
These authors had contributed this manuscript equally.
Received: 19 August 2019 / Revised: 30 August 2019 / Accepted: 4 September 2019 / Published: 11 September 2019
Carbapenem-resistant Enterobacteriaceae are a significant threat to public health, and a major resistance determinant that promotes this phenotype is the production of the OXA-48 carbapenemase. The activity of OXA-48 towards carbapenems is a puzzling phenotype as its hydrolytic activity against doripenem is non-detectable. To probe the mechanistic basis for this observation, we determined the 1.5 Å resolution crystal structure of the deacylation deficient K73A variant of OXA-48 in complex with doripenem. Doripenem is observed in the Δ1R and Δ1S tautomeric states covalently attached to the catalytic S70 residue. Likely due to positioning of residue Y211, the carboxylate moiety of doripenem is making fewer hydrogen bonding/salt-bridge interactions with R250 compared to previously determined carbapenem OXA structures. Moreover, the hydroxyethyl side chain of doripenem is making van der Waals interactions with a key V120 residue, which likely affects the deacylation rate of doripenem. We hypothesize that positions V120 and Y211 play important roles in the carbapenemase profile of OXA-48. Herein, we provide insights for the further development of the carbapenem class of antibiotics that could render them less effective to hydrolysis by or even inhibit OXA carbapenemases. View Full-Text
Keywords: carbapenemase; structural biology; OXA-48; carbapenem-resistant Enterobacteriaceae carbapenemase; structural biology; OXA-48; carbapenem-resistant Enterobacteriaceae
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MDPI and ACS Style

Papp-Wallace, K.M.; Kumar, V.; Zeiser, E.T.; Becka, S.A.; van den Akker, F. Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem. Antibiotics 2019, 8, 145. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030145

AMA Style

Papp-Wallace KM, Kumar V, Zeiser ET, Becka SA, van den Akker F. Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem. Antibiotics. 2019; 8(3):145. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030145

Chicago/Turabian Style

Papp-Wallace, Krisztina M., Vijay Kumar, Elise T. Zeiser, Scott A. Becka, and Focco van den Akker. 2019. "Structural Analysis of The OXA-48 Carbapenemase Bound to A “Poor” Carbapenem Substrate, Doripenem" Antibiotics 8, no. 3: 145. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8030145

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