On the Offensive: the Role of Outer Membrane Vesicles in the Successful Dissemination of New Delhi Metallo-beta-lactamase (NDM-1)


Posted: 2021-09-28 19:00:00
. 2021 Sep 28;e0183621. doi: 10.1128/mBio.01836-21. Online ahead of print. Affiliations Expand Affiliations 1 Laboratorio de Microbiología Molecular, Instituto de Microbiología Básica y Aplicada, Universidad Nacional de Quilmes, Bernal, Buenos Aires, Argentina. 2 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. 3 Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA. 4 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 5 Medical Service and GRECC, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA. 6 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA. 7 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 8 Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 9 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 10 Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 11 Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina. 12 Área Biofísica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina. 13 Universidad Nacional de Hurlingham, Villa Tesei, Buenos Aires, Argentina. # Contributed equally. Item in Clipboard Melina M B Martínez et al. mBio. 2021. Show details Display options Display options Format . 2021 Sep 28;e0183621. doi: 10.1128/mBio.01836-21. Online ahead of print. Affiliations 1 Laboratorio de Microbiología Molecular, Instituto de Microbiología Básica y Aplicada, Universidad Nacional de Quilmes, Bernal, Buenos Aires, Argentina. 2 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. 3 Research Service, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA. 4 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 5 Medical Service and GRECC, Veterans Affairs Northeast Ohio Healthcare System, Cleveland, Ohio, USA. 6 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio, USA. 7 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 8 Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 9 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 10 Department of Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 11 Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Rosario, Argentina. 12 Área Biofísica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina. 13 Universidad Nacional de Hurlingham, Villa Tesei, Buenos Aires, Argentina. # Contributed equally. Item in Clipboard CiteDisplay options Display options Format Abstract The 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. Keywords: E. coli; Galleria mellonella; NDM; NDM-1 carbapenemase; P. aeruginosa; cross-species protection; metallo-β-lactamase; outer membrane vesicles.

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