On the offensive: the role of outer membrane vesicles in the successful dissemination of New Delhi Metallo-β-lactamase (NDM-1)

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dc.citation.titlemBio
dc.citation.volume12
dc.contributor.orcidhttps://orcid.org/0000-0002-4007-8721
dc.contributor.orcidhttps://orcid.org/0000-0002-3299-894X
dc.contributor.orcidhttps://orcid.org/0000-0002-7978-3233
dc.contributor.orcidhttps://orcid.org/0000-0001-7423-2646
dc.contributor.orcidhttps://orcid.org/0000-0002-0575-1810
dc.creatorMartínez, Melina María Belén
dc.creatorBonomo, Robert A.
dc.creatorVila, Alejandro J.
dc.creatorMaffía, Paulo César
dc.creatorGonzález, Lisandro Javier
dc.date.accessioned2024-11-08T11:35:35Z
dc.date.available2024-11-08T11:35:35Z
dc.date.issued2021-09-28
dc.description.abstractThe emergence and worldwide dissemination of carbapenemase-producing Gram-negative bacteria are a major public health threat. Metallo-β-lactamases (MBLs) represent the largest family of carbapenemases. Regrettably, these resistance determinants are spreading worldwide. Among them, the New Delhi metallo-β-lactamase (NDM-1) is experiencing the fastest and largest geographical spread. NDM-1 β-lactamase is anchored to the bacterial outer membrane, while most MBLs are soluble, periplasmic enzymes. This unique cellular localization favors the selective secretion of active NDM-1 into outer membrane vesicles (OMVs). Here, we advance the idea that NDM-containing vesicles serve as vehicles for the local dissemination of NDM-1. We show that OMVs with NDM-1 can protect a carbapenem-susceptible strain of Escherichia coli upon treatment with meropenem in a Galleria mellonella infection model. Survival curves of G. mellonella revealed that vesicle encapsulation enhances the action of NDM-1, prolonging and favoring bacterial protection against meropenem inside the larva hemolymph. We also demonstrate that E. coli cells expressing NDM-1 protect a susceptible Pseudomonas aeruginosa strain within the larvae in the presence of meropenem. By using E. coli variants engineered to secrete variable amounts of NDM-1, we demonstrate that the protective effect correlates with the amount of NDM-1 secreted into vesicles. We conclude that secretion of NDM-1 into OMVs contributes to the survival of otherwise susceptible nearby bacteria at infection sites. These results disclose that OMVs play a role in the establishment of bacterial communities, in addition to traditional horizontal gene transfer mechanisms. IMPORTANCE: Resistance to carbapenems, last-resort antibiotics, is spreading worldwide, raising great concern. NDM-1 is one of the most potent and widely disseminated carbapenem-hydrolyzing enzymes spread among many bacteria and is secreted to the extracellular medium within outer membrane vesicles. We show that vesicles carrying NDM-1 can protect carbapenem-susceptible strains of E. coli and P. aeruginosa upon treatment with meropenem in a live infection model. These vesicles act as nanoparticles that encapsulate and transport NDM-1, prolonging and favoring its action against meropenem inside a living organism. Secretion of NDM-1 into vesicles contributes to the survival of otherwise susceptible nearby bacteria at infection sites. We propose that vesicles play a role in the establishment of bacterial communities and the dissemination of antibiotic resistance, in addition to traditional horizontal gene transfer mechanisms.
dc.description.filFil: Martínez, Melina María Belén. Universidad Nacional de Quilmes. Instituto de Microbiología Básica y Aplicada (IMBA). Laboratorio de Microbiología Molecular; Argentina.
dc.description.filFil: Martínez, Melina María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.
dc.description.filFil: Bonomo, Robert A. Veterans Affairs Northeast Ohio Healthcare System. Research Service; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics; United States.
dc.description.filFil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. GRECC. Medical Service; United States.
dc.description.filFil: Vila, Alejandro J. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET). Área Biofísica; Argentina.
dc.description.filFil: Maffía, Paulo César. Universidad Nacional de Quilmes. Instituto de Microbiología Básica y Aplicada (IMBA). Laboratorio de Microbiología Molecular; Argentina.
dc.description.filFil: Maffía, Paulo César. Universidad Nacional de Hurlingham; Argentina.
dc.description.filFil: Maffía, Paulo César. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Argentina.
dc.description.filFil: González, Lisandro Javier. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET). Área Biofísica; Argentina.
dc.description.sponsorshipNational Institutes of Health (NIH): R01AI100560, R01AI063517, R01AI072219
dc.description.sponsorshipAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (Agencia I+D+i)
dc.description.sponsorshipCleveland Department of Veterans Affairs
dc.description.sponsorshipBiomedical Laboratory Research & Development Service of the VA Office of Research and Development: award number 1I01BX001974
dc.description.sponsorshipGeriatric Research Education and Clinical Center VISN 10
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
dc.description.versionpeerreviewed
dc.format.extent1-13
dc.identifier.citationMartínez, M. M. B., Bonomo, R. A., Vila, A. J., Maffía, P. C. and González, L. J. (2021). On the offensive: the role of outer membrane vesicles in the successful dissemination of New Delhi Metallo-β-lactamase (NDM-1). mBio, 12(5). https://doi.org/10.1128/mbio.01836-21
dc.identifier.e-issn2150-7511
dc.identifier.issn2161-2129
dc.identifier.urihttps://hdl.handle.net/2133/28068
dc.language.isoen
dc.publisherAmerican Society for Microbiology
dc.relation.publisherversionhttps://doi.org/10.1128/mbio.01836-21
dc.relation.publisherversionhttps://journals.asm.org/doi/10.1128/mbio.01836-21
dc.rightsopenAccess
dc.rights.holderMartínez, Melina María Belén
dc.rights.holderBonomo, Robert A.
dc.rights.holderVila, Alejandro J.
dc.rights.holderMaffía, Paulo César
dc.rights.holderGonzález, Lisandro Javier
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectOuter membrane vesicles
dc.subjectNDM-1 carbapenemase
dc.subjectCross-species protection
dc.subjectGalleria mellonella
dc.subjectEscherichia coli
dc.subjectPseudomonas aeruginosa
dc.subjectMetallo-β-lactamases
dc.subjectNDM
dc.titleOn the offensive: the role of outer membrane vesicles in the successful dissemination of New Delhi Metallo-β-lactamase (NDM-1)
dc.typearticulo
dc.type.versionpublishedVersion

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