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dc.contributor.authorVallejo Vidal, Juan Andrés
dc.contributor.authorMartínez Guitián, Marta
dc.contributor.authorVázquez Ucha, Juan Carlos
dc.contributor.authorGonzález Bello, Concepción
dc.contributor.authorPoza, Margarita
dc.contributor.authorBuynak, John
dc.contributor.authorBethel, Christopher R.
dc.contributor.authorBonomo, Roberto A.
dc.contributor.authorBou, Germán
dc.contributor.authorBeceiro Casas, Alejandro
dc.date.accessioned2018-07-03T10:45:05Z
dc.date.available2018-07-03T10:45:05Z
dc.date.issued2016-04-28
dc.identifier.citationJuan A. Vallejo, Marta Martínez-Guitián, Juan C. Vázquez-Ucha, Concepción González-Bello, Margarita Poza, John D. Buynak, Christopher R. Bethel, Robert A. Bonomo, German Bou, Alejandro Beceiro; LN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48, Journal of Antimicrobial Chemotherapy, Volume 71, Issue 8, 1 August 2016, Pages 2171–2180, https://doi.org/10.1093/jac/dkw105
dc.identifier.issn0305-7453
dc.identifier.urihttp://hdl.handle.net/10347/16935
dc.descriptionThis is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record Juan A. Vallejo, Marta Martínez-Guitián, Juan C. Vázquez-Ucha, Concepción González-Bello, Margarita Poza, John D. Buynak, Christopher R. Bethel, Robert A. Bonomo, German Bou, Alejandro Beceiro; LN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48, Journal of Antimicrobial Chemotherapy, Volume 71, Issue 8, 1 August 2016, Pages 2171–2180 is available online at: https://doi.org/10.1093/jac/dkw105
dc.description.abstractObjectives Carbapenemases are the most important mechanism responsible for carbapenem resistance in Enterobacteriaceae. Among carbapenemases, OXA-48 presents unique challenges as it is resistant to β-lactam inhibitors. Here, we test the capacity of the compound LN-1-255, a 6-alkylidene-2′-substituted penicillanic acid sulfone, to inhibit the activity of the carbapenemase OXA-48. Methods The OXA-48 gene was cloned and expressed in Klebsiella pneumoniae and Escherichia coli in order to obtain MICs in the presence of inhibitors (clavulanic acid, tazobactam and sulbactam) and LN-1-255. OXA-48 was purified and steady-state kinetics was performed with LN-1-255 and tazobactam. The covalent binding mode of LN-1-255 with OXA-48 was studied by docking assays. Results Both OXA-48-producing clinical and transformant strains displayed increased susceptibility to carbapenem antibiotics in the presence of 4 mg/L LN-1-255 (2–32-fold increased susceptibility) and 16 mg/L LN-1-255 (4–64-fold increased susceptibility). Kinetic assays demonstrated that LN-1-255 is able to inhibit OXA-48 with an acylation efficiency (k2/K) of 10 ± 1 × 104 M−1 s−1 and a slow deacylation rate (koff) of 7 ± 1 × 10−4 s−1. IC50 was 3 nM for LN-1-255 and 1.5 μM for tazobactam. Lastly, kcat/kinact was 500-fold lower for LN-1-255 than for tazobactam. Conclusions In these studies, carbapenem antibiotics used in combination with LN-1-255 are effective against the carbapenemase OXA-48, an important emerging mechanism of antibiotic resistance. This provides an incentive for further investigations to maximize the efficacy of penicillin sulfone inhibition of class D plasmid-carried Enterobacteriaceae carbapenemases.
dc.description.sponsorshipThis work was supported by the Spanish National Plans for Scientific Research, Development and Technological Innovation 2013-16 and funded by the ISCIII-General Subdirection of Assessment and Promotion of the Research-European Regional Development Fund (ERDF) ‘A way of making Europe’: PI12/00552 to G. B. and PI14/00059 to M. P. and A. B. Also, research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (USA) under Award Numbers R01AI100560, R01AI063517 and R01AI072219 to R. A. B. This study was supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs (USA), Award Number 1I01BX001974 to R. A. B. from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development and the Geriatric Research Education and Clinical Center VISN 10 (USA) to R. A. B. This study was also supported by the Spanish Ministry of Economy and Competiveness (SAF2013-42899-R), Xunta de Galicia (Spain) (GRC2013-041) and the European Regional Development Fund (ERDF) to C. G.-B, and supported by National Institutes of Health (USA) to J. D. B. (1R15AI109624). J. V. A. was financially supported by the Sara Borrell Programme ISCIII-FEDER (CD13/00373). J. V. H. and A. B. were financially supported by the Miguel Servet Programme ISCIII-FEDER (CP13/00226)
dc.language.isoeng
dc.publisherOxford University Press
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-42899-R/ES/DESARROLLO DE NUEVOS ANTIBIOTICOS PARA EL TRATAMIENTO DE INFECCIONES BACTERIANAS RESISTENTES: METABOLISMO, RESISTENCIA Y COMUNICACION CELULA-CELULA
dc.rights© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved
dc.subjectSteady state
dc.subjectPlasmids
dc.subjectAntibiotic resistance
dc.subjectBacterial
dc.subjectPenicillin
dc.subjectCarbapenem
dc.subjectAcylation
dc.subjectClavulanic acid
dc.subjectEnterobacteriaceae
dc.subjectGenes
dc.subjectKlebsiella pneumoniae
dc.subjectLactams
dc.subjectMechlorethamine
dc.subjectNew mexico
dc.subjectSulbactam
dc.subjectSulfones
dc.subjectKinetics
dc.subjectEscherichia coli
dc.subjectTazobactam
dc.subjectIncentives
dc.subjectMalnutrition-inflammation-cachexia syndrome
dc.subjectCarbapenem resistance
dc.titleLN-1-255, a penicillanic acid sulfone able to inhibit the class D carbapenemase OXA-48
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.1093/jac/dkw105
dc.relation.publisherversionhttps://doi.org/10.1093/jac/dkw105
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.identifier.e-issn1460-2091
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI


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