Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance
Digital
- Autores:
-
Fuentes-Lopera, Andrés Felipe
Sánchez-Barbosa, Daniela
- Tipo de recurso:
- Trabajo de grado de pregrado
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Santander
- Repositorio:
- Repositorio Universidad de Santander
- Idioma:
- spa
- OAI Identifier:
- oai:repositorio.udes.edu.co:001/10380
- Palabra clave:
- Bacterias Gramnegativas
Endopeptidasas
Resistencia betalactámica
Variación genética
Escherichia coli
Gram-negative bacteria
Endopeptidases
Beta-lactam resistance
Genetic variation
- Rights
- embargoedAccess
- License
- http://purl.org/coar/access_right/c_f1cf
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| dc.title.spa.fl_str_mv |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| dc.title.translated.none.fl_str_mv |
Genetic Diversity of Metallobetalactamase New Delhi in Escherichia coli: A Scoping Review |
| title |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| spellingShingle |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance Bacterias Gramnegativas Endopeptidasas Resistencia betalactámica Variación genética Escherichia coli Gram-negative bacteria Endopeptidases Beta-lactam resistance Genetic variation |
| title_short |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| title_full |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| title_fullStr |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| title_full_unstemmed |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| title_sort |
Diversidad Genética de la Metalobetalactamasa New Delhi en Escherichia coli: Revisión de Alcance |
| dc.creator.fl_str_mv |
Fuentes-Lopera, Andrés Felipe Sánchez-Barbosa, Daniela |
| dc.contributor.advisor.none.fl_str_mv |
Trejos-Suárez, Juanita |
| dc.contributor.author.none.fl_str_mv |
Fuentes-Lopera, Andrés Felipe Sánchez-Barbosa, Daniela |
| dc.contributor.jury.none.fl_str_mv |
Méndez-Diaz, Luz Mery Arias Guerrero, Monica |
| dc.contributor.researchgroup.none.fl_str_mv |
Instituto de Investigaciones MASIRA |
| dc.subject.proposal.spa.fl_str_mv |
Bacterias Gramnegativas Endopeptidasas Resistencia betalactámica Variación genética |
| topic |
Bacterias Gramnegativas Endopeptidasas Resistencia betalactámica Variación genética Escherichia coli Gram-negative bacteria Endopeptidases Beta-lactam resistance Genetic variation |
| dc.subject.proposal.other.fl_str_mv |
Escherichia coli |
| dc.subject.proposal.eng.fl_str_mv |
Gram-negative bacteria Endopeptidases Beta-lactam resistance Genetic variation |
| description |
Digital |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023-06-05 |
| dc.date.accessioned.none.fl_str_mv |
2024-05-09T15:40:39Z |
| dc.date.available.none.fl_str_mv |
2024-05-09T15:40:39Z 2025-09-29 |
| dc.type.none.fl_str_mv |
Trabajo de grado - Pregrado |
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http://purl.org/coar/resource_type/c_7a1f |
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http://purl.org/coar/version/c_71e4c1898caa6e32 |
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Text |
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info:eu-repo/semantics/bachelorThesis |
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info:eu-repo/semantics/submittedVersion |
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http://purl.org/coar/resource_type/c_7a1f |
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Universidad de Santander |
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T 17.23 F826d |
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Repositorio Digital Institucional Universidad de Santander |
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https://repositorio.udes.edu.co |
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https://repositorio.udes.edu.co/handle/001/10380 |
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Universidad de Santander T 17.23 F826d Repositorio Digital Institucional Universidad de Santander |
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https://repositorio.udes.edu.co https://repositorio.udes.edu.co/handle/001/10380 |
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spa |
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Association of the emerging carbapenemase NDM-1 with a bleomycin resistance protein in Enterobacteriaceae and Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 56(4), 1693–1697. https://doi.org/10.1128/aac.05583-11 Savard, P., Gopinath, R., Zhu, W., et al. (2011). First NDM-Positive Salmonella sp. Strain Identified in the United States. Antimicrobial Agents and Chemotherapy, 55(12), 5957–5958. https://doi.org/10.1128/aac.05719-11 Poirel, L., Fortineau, N., & Nordmann, P. (2011). International transfer of NDM-1-producing Klebsiella pneumoniae from Iraq to France. Antimicrobial Agents and Chemotherapy, 55(4), 1821–1822. https://doi.org/10.1128/aac.01761-10 Kaase, M., Nordmann, P., Wichelhaus, T. A., et al. (2011). NDM-2 carbapenemase in Acinetobacter baumannii from Egypt. The Journal of Antimicrobial Chemotherapy, 66(6), 1260–1262. https://doi.org/10.1093/jac/dkr135 Mulvey, M. R., Grant, J. M., Plewes, K., et al. (2011). 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Journal of Global Antimicrobial Resistance, 29, 20–22. https://doi.org/10.1016/j.jgar.2022.01.009 Ariyoshi, T., Aoki, K., Kubota, H., et al. (2022). Molecular characterization of bla NDM -carrying IncX3 plasmids: bla NDM-16b likely emerged from a mutation of bla NDM-5 on IncX3 Plasmid. Microbiology Spectrum, 10(4). https://doi.org/10.1128/spectrum.01449-22 Zheng,Z. & Ye,L. (2021). Subclass B1 metallo-beta-lactamase NDM-34 [Vibrio parahaemolyticus]. https://www.ncbi.nlm.nih.gov/protein/QVU28093.1 (accessed 2023 May 28) Poirel, L., Ortiz de la Rosa, J. M., Sakaoglu, Z., et al. (2022). NDM-35-producing ST167 Escherichia coli highly resistant to β-lactams including cefiderocol. Antimicrobial Agents and Chemotherapy, 66(8). https://doi.org/10.1128/aac.00311-22 Ma, W., Zhu, B., Wang, W., et al. (2023). Genetic and enzymatic characterization of two novel blaNDM-36, -37 variants in Escherichia coli strains. European Journal of Clinical Microbiology & Infectious Diseases: Official Publication of the European Society of Clinical Microbiology, 42(4), 471–480. https://doi.org/10.1007/s10096-023-04576-y Li, H. & Wise, M. (2021). Subclass B1 metallo-beta-lactamase NDM-38 [Providencia rettgeri]. https://www.ncbi.nlm.nih.gov/protein/QWO25674.1 (accessed 2023 May 28) Mataseje, L., Boyd, D., & Mulvey, M. (2021). Subclass B1 metallo-beta-lactamase NDM-39 [Klebsiella pneumoniae].https://www.ncbi.nlm.nih.gov/protein/QYZ89892.1 (accessed 2023 May 28) Mataseje, L., Boyd, D. & Mulvey, M. (2021). Subclass B1 metallo-beta-lactamase NDM-40 [Acinetobacter baumannii]. https://www.ncbi.nlm.nih.gov/protein/QYZ89893.1 (accessed 2023 May 28) Wen,H., Feng,Y. and Zong,Z. (2021). Subclass B1 metallo-beta-lactamase NDM-41 (plasmid) [Klebsiella pneumoniae]. https://www.ncbi.nlm.nih.gov/protein/UAX43328.1 (accessed 2023 May 28) Quiñones Pérez, D., Aung, M. S., Carmona Cartaya, Y., et al. (2022). Clonal diversity of Acinetobacter clinical isolates producing NDM-type carbapenemase in Cuba, 2013–19. IJID Regions (Online), 5, 93–96. https://doi.org/10.1016/j.ijregi.2022.08.008 Pardeshenas,M., Shahri,M., Khodakarami,F., & Kalantar-Neyestanaki,D. (2022). Subclass B1 metallo-beta-lactamase NDM-43 [Klebsiella pneumoniae]. https://www.ncbi.nlm.nih.gov/protein/UTQ48691.1 (accessed 2023 May 28) Hamed,S.L. & Hasoon,N.A. (2022) Subclass B1 metallo-beta-lactamase NDM-44 [Klebsiella pneumoniae]. https://www.ncbi.nlm.nih.gov/protein/UVJ50740.1 (accessed 2023 May 28) Zhai, Y., Lee, S., Teng, L., et al. (2021). Dissemination mechanisms of NDM genes in hospitalized patients. JAC-Antimicrobial Resistance, 3(1). https://doi.org/10.1093/jacamr/dlab032 Takayama, Y., Sekizuka, T., Matsui, H., et al. (2020). Characterization of the IncFII-IncFIB(pB171) Plasmid carrying blaNDM-5 in Escherichia coli ST405 clinical isolate in japan. Infection and Drug Resistance, 13, 561–566. https://doi.org/10.2147/idr.s232943 Naeem, S., Bilal, H., Muhammad, H., et al. (2021). Detection of blaNDM-1 gene in ESBL producing Escherichia coli and Klebsiella pneumoniae isolated from urine samples. Journal of infection in developing countries, 15(04), 516–522. https://doi.org/10.3855/jidc.12850 Tsilipounidaki, K., Florou, Z., Skoulakis, A., et al. (2023). Diversity of bacterial clones and plasmids of NDM-1 producing Escherichia coli clinical isolates in Central Greece. Microorganisms, 11(2), 516. https://doi.org/10.3390/microorganisms11020516 Muggeo, A., Maiga, A., Maiga, I., et al. (2020). First description of IncX3 NDM-5-producing plasmid within Escherichia coli ST448 in Mali. Journal of Medical Microbiology, 69(5), 685–688. https://doi.org/10.1099/jmm.0.001182 Harada, S., Suzuki, M., Sasaki, T., Sakurai, A., Inaba, M., Takuya, H., Wakuda, M., & Doi, Y. (2021). Transmission of NDM-5-producing and OXA-48-producing Escherichia coli sequence type 648 by international visitors without previous medical exposure. Microbiology Spectrum, 9(3). https://doi.org/10.1128/spectrum.01827-21 Haeili, M., Barmudeh, S., Omrani, M., et al. (2023). Whole-genome sequence analysis of clinically isolated carbapenem resistant Escherichia coli from Iran. BMC Microbiology, 23(1). https://doi.org/10.1186/s12866-023-02796-y Huang, L., Hu, H., Xu, C., et al. (2023). Characterization of NDM-5-producing Escherichia coli strains isolated from pediatric patients with bloodstream infections in a Chinese hospital. Genes, 14(2), 520. https://doi.org/10.3390/genes14020520 Kulp, A., & Kuehn, M. J. (2010). Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annual Review of Microbiology, 64(1), 163–184. https://doi.org/10.1146/annurev.micro.091208.073413 Lee, J., Kim, O., & Gho, Y. (2016). Proteomic profiling of Gram‐negative bacterial outer membrane vesicles: Current perspectives. Proteomics. Clinical Applications, 10(9–10), 897–909. https://doi.org/10.1002/prca.201600032 López, C., Prunotto, A., Bahr, G., et al. (2021). Specific protein-membrane interactions promote packaging of metallo-β-lactamases into outer membrane vesicles. Antimicrobial Agents and Chemotherapy, 65(10). https://doi.org/10.1128/aac.00507-21 Martínez, M., Bonomo, R., Vila, A., et al. (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 Khan, A., Maryam, L., & Zarrilli, R. (2017). Structure, Genetics and Worldwide Spread of New Delhi Metallo-β-lactamase (NDM): a threat to public health. BMC Microbiology, 17(1). https://doi.org/10.1186/s12866-017-1012-8 Barton, C. (2019). Introduction. One Health: over a decade of progress on the road to sustainability: -EN- -FR- Introduction. Une seule santé : plus d’une décennie d’avancées vers la durabilité -ES- Introducción. Una sola salud: más de un decenio de avances en la senda de la sostenibilidad. Revue scientifique et technique (International Office of Epizootics), 38(1), 21–50. https://doi.org/10.20506/rst.38.1.2939 Park, Y., Choi, Q., Kwon, G. C., & Koo, S. H. (2020). Emergence and transmission of New Delhi metallo‐beta‐lactamase‐5‐producing Escherichia coli Sequence Type 361 in a Tertiary Hospital in South Korea. Journal of Clinical Laboratory Analysis, 34(2). https://doi.org/10.1002/jcla.23041 Rousham, E., Asaduzzaman, M., Mozmader, T, et al. (2021). Human colonization with extended-spectrum beta-lactamase-producing E. coli in relation to animal and environmental exposures in Bangladesh: An observational one health study. Environmental Health Perspectives, 129(3). https://doi.org/10.1289/ehp7670 Lüneberg, K., Amábile-Cuevas, C, Mucito-Varela, E., et al. (2022). Metallo-beta-lactamase-producing Escherichia coli in the sewage of Mexico City: where do they come from? Canadian Journal of Microbiology, 68(2), 139–145. https://doi.org/10.1139/cjm-2021-0284 |
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Trejos-Suárez, Juanitab654cd2e-011c-4bdb-a2a5-15263cdaac76600Fuentes-Lopera, Andrés Felipefc28f410-787d-498b-aa2e-52e7a2d18eaa-1Sánchez-Barbosa, Danielabe35b0af-200d-44e9-8421-10ade70be7d3-1Méndez-Diaz, Luz Mery6c309546-763e-47a4-b153-87c2e7113ef6-1Arias Guerrero, Monicaa17e125d-3e6e-493a-8ee4-4bd815b584fd-1Instituto de Investigaciones MASIRA2024-05-09T15:40:39Z2025-09-292024-05-09T15:40:39Z2023-06-05DigitalEl descubrimiento global de bacterias portadoras de New Delhi Metalobetalactamasa (NDM) ha surgido como un alarmante problema de salud pública, asociado a la migración transcontinental y al aumento de la mortalidad por enfermedades infecciosas. Bacterias Gramnegativas, como Escherichia coli, presentan desafíos significativos en el tratamiento debido a la limitada disponibilidad de opciones terapéuticas. Se abarcaron bases de datos como Pubmed, Scopus, Google Scholar, EBSCO HOST, OVIDSP, ProQuest y Metarevistas, y clasificó los documentos obtenidos en fuentes primarias, secundarias y terciarias. El período analizado abarcó los últimos 18 años desde la primera descripción de NDM-1, y tuvo como objetivo principal describir la diversidad genética de esta enzima. En esta revisión se identificaron 44 variacionestranscripcionales del gen blaNDM-1, se exploró la estructura y función de la enzima,se analizó el papel de las vesículas de membrana externas en la transferencia de NDM, y se resaltó la importancia del enfoque "una sola salud" en el control de la diseminación de este gen. Se concluye que, aunque existen varias estrategias para abordar la resistencia a los antibióticos que deben considerarse por las autoridades sanitarias, se requieren estudios adicionales para llenar los vacíos de conocimiento y mejorar la comprensión de esta creciente amenaza.The global discovery of bacteria carrying New Delhi Metallo-beta-lactamase (NDM) has emerged as a concerning public health issue, linked to transcontinental migration and an increase in mortality from infectious diseases. Gram-negative bacteria, such as Escherichia coli, pose significant challenges for treatment due to the limited availability of therapeutic options. Various databases including PubMed, Scopus, Google Scholar, EBSCO HOST, OVIDSP, ProQuest, and Metarevistas were included, and the obtained documents were classified as primary, secondary, and tertiary sources. The analysisspanned the last 18 years since the initial identification of NDM-1, with the main objective being to describe the genetic diversity of this enzyme. This review identified 44 transcriptional variations of the blaNDM-1 gene, explored the structure and function of the enzyme, discussed the role of outer membrane vesicles in NDM transfer, and emphasized the importance of the "one-health" approach in controlling the spread of this gene in public health. It is concluded that while there are several strategies to address antibiotic resistance that should be considered by health authorities, additional studies are required to bridge knowledge gaps and enhance understanding of this growing threat.PregradoBacteriólogo(a) y Laboratorista ClínicoEnfermedades Infecciosas22 papplication/pdfapplication/mswordUniversidad de SantanderT 17.23 F826dRepositorio Digital Institucional Universidad de Santanderhttps://repositorio.udes.edu.cohttps://repositorio.udes.edu.co/handle/001/10380spaUniversidad de SantanderBucaramangaFacultad de Ciencias Médicas y de la SaludBucaramanga, ColombiaBacteriología y Laboratorio ClínicoBedenić, B., Sardelić, S., Luxner, J., et al. (2016). Molecular characterization of class b carbapenemases in advanced stage of dissemination and emergence of class d carbapenemases in Enterobacteriaceae from Croatia. Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, 43, 74–82. https://doi.org/10.1016/j.meegid.2016.05.011Van Duin, D., & Doi, Y. (2017). The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence, 8(4), 460–469. https://doi.org/10.1080/21505594.2016.1222343Raghunath, D. (2010). New metallo β-lactamase NDM-1. The Indian Journal of Medical Research, 132, 478–481.Rolain, J. M., Parola, P., & Cornaglia, G. (2010). New Delhi metallo-beta-lactamase (NDM-1): towards a new pandemia? Clinical Microbiology and Infection: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 16(12), 1699–1701. https://doi.org/10.1111/j.1469-0691.2010.03385.xWalsh, T. R., Weeks, J., Livermore, D. M., et al. (2011). Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. The Lancet Infectious Diseases, 11(5), 355–362. https://doi.org/10.1016/S1473-3099(11)70059-7Solé, M., Pitart, C., Roca, I., et al. (2011). First description of an Escherichia coli strain producing NDM-1 carbapenemase in Spain. Antimicrobial Agents and Chemotherapy, 55(9), 4402–4404. https://doi.org/10.1128/AAC.00642-11Choi, Y. J., Kim, Y. A., Junglim, K., et al. (2023). Emergence of NDM-1-producing Pseudomonas aeruginosa sequence type 773 clone: Shift of carbapenemase molecular epidemiology and spread of 16S rRNA methylase genes in Korea. Annals of Laboratory Medicine, 43(2), 196–199. https://doi.org/10.3343/alm.2023.43.2.196Maaroufi, R., Dziri, O., Hadjadj, L., et al. (2021). Occurrence of NDM-1 and VIM-2 co-producing Escherichia coli and OprD alteration in Pseudomonas aeruginosa isolated from hospital environment samples in northwestern Tunisia. Diagnostics (Basel, Switzerland), 11(9), 1617. https://doi.org/10.3390/diagnostics11091617Warnes, S. L., Highmore, C. J., & Keevil, C. W. (2012). Horizontal transfer of antibiotic resistance genes on abiotic touch surfaces: Implications for public health. mBio, 3(6). https://doi.org/10.1128/mbio.00489-12Kumarasamy, K. K., Toleman, M. A., Walsh, T. R., et al. (2010). Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. The Lancet Infectious Diseases, 10(9), 597–602. https://doi.org/10.1016/s1473-3099(10)70143-2Dortet, L., Nordmann, P., & Poirel, L. (2012). Association of the emerging carbapenemase NDM-1 with a bleomycin resistance protein in Enterobacteriaceae and Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy, 56(4), 1693–1697. https://doi.org/10.1128/aac.05583-11Savard, P., Gopinath, R., Zhu, W., et al. (2011). First NDM-Positive Salmonella sp. Strain Identified in the United States. Antimicrobial Agents and Chemotherapy, 55(12), 5957–5958. https://doi.org/10.1128/aac.05719-11Poirel, L., Fortineau, N., & Nordmann, P. (2011). International transfer of NDM-1-producing Klebsiella pneumoniae from Iraq to France. Antimicrobial Agents and Chemotherapy, 55(4), 1821–1822. https://doi.org/10.1128/aac.01761-10Kaase, M., Nordmann, P., Wichelhaus, T. A., et al. (2011). NDM-2 carbapenemase in Acinetobacter baumannii from Egypt. The Journal of Antimicrobial Chemotherapy, 66(6), 1260–1262. https://doi.org/10.1093/jac/dkr135Mulvey, M. R., Grant, J. M., Plewes, K., et al. (2011). New Delhi Metallo-β-Lactamase inKlebsiella pneumoniae and Escherichia coli ,Canada. Emerging infectious diseases, 17(1), 103–106. https://doi.org/10.3201/eid1701.101358Chen, Z., Wang, Y., Tian, L., et al. (2015). First report in China of Enterobacteriaceae clinical isolates coharboring blaNDM-1 and blaIMP-4 drug resistance genes. Microbial Drug Resistance (Larchmont, N.Y.), 21(2), 167–170. https://doi.org/10.1089/mdr.2014.0087Poirel, L., Schrenzel, J., Cherkaoui, A., et al. (2011). Molecular analysis of NDM-1-producing enterobacterial isolates from Geneva, Switzerland. The Journal of Antimicrobial Chemotherapy, 66(8), 1730–1733. https://doi.org/10.1093/jac/dkr174Yamamoto, T., Takano, T., Iwao, Y., et al. (2011). Emergence of NDM-1-positive capsulated Escherichia coli with high resistance to serum killing in Japan. Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy, 17(3), 435–439. https://doi.org/10.1007/s10156-011-0232-3Camara, L. (2020). Carbapenemasa nueva delhi tipo 1 (ndm): descripción fenotípica y epidemiológica. [Tesis doctoral, Universidad Peruana Cayetano Heredia]. Repositorio UPCH. https://repositorio.upch.edu.pe/bitstream/handle/20.500.12866/8572/Carbapenemasa_CamaraLopez_Lizet.pdf?sequence=1&isAllowed=yCorrea, C., Castro, E., Salamanca, D., et al. (2016). Escherichia coli productora de Nueva Delhi metalo-β-lactamasa en Colombia: reporte de caso. Infectio: revista de la Asociacion Colombiana de Infectologia. https://doi.org/10.1016/j.infect.2016.05.002Enrique, M., Durán, M., Patricia, A., et al. (2013). Circulación de Carbapenemasas tipo New Delhi Metalo-βlactamasa (NDM), Colombia, 2011 a 2013. Recuperado el 6 de junio de 2023, de https://www.ins.gov.co/buscador/IQEN/IQEN%20vol%2018%202013%20num%2011.pdfLi, J., Bi, Z., Ma, S., et al. (2019). Inter-host transmission of carbapenemase-producing Escherichia coli among humans and backyard animals. Environmental Health Perspectives, 127(10). https://doi.org/10.1289/ehp5251Berrazeg, M., Diene, S. M., Medjahed, L., et al. (2014). New Delhi Metallo-beta-lactamase around the world: An eReview using Google Maps. Euro Surveillance : Bulletin Europeen Sur Les Maladies Transmissibles [Euro Surveillance : European Communicable Disease Bulletin], 19(20). https://doi.org/10.2807/1560-7917.es2014.19.20.20809Vera-Leiva, A., Barría-Loaiza, C., Carrasco-Anabalón, S., et al. (2017). KPC: Klebsiella pneumoniae carbapenemasa, principal carbapenemasa en enterobacterias. Revista Chilena de Infectologia: Organo Oficial de La Sociedad Chilena de Infectologia, 34(5), 476–484. https://doi.org/10.4067/s0716-10182017000500476Khong, W. X., Xia, E., Marimuthu, K., et al. (2016). Local transmission and global dissemination of New Delhi Metallo-Beta-Lactamase (NDM): a whole genome analysis. BMC Genomics, 17(1). https://doi.org/10.1186/s12864-016-2740-0Jean, S.-S., Harnod, D., & Hsueh, P.-R. (2022). Global threat of carbapenem-resistant Gram-negative bacteria. Frontiers in cellular and infection microbiology, 12. https://doi.org/10.3389/fcimb.2022.823684Patel, S. (2012). NDM-1: ¿el nuevo supermicrobio? Nursing, 30(7), 46. https://doi.org/10.1016/s0212-5382(12)70105-xAntimicrobial resistance: revisiting the “tragedy of the commons”. (2010). Bulletin of the World Health Organization, 88(11), 805–806. https://doi.org/10.2471/blt.10.031110Chen, C.-J., Wu, T.-L., Lu, P.-L., et al. 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Resistance of Klebsiella pneumoniae strains carrying blaNDM–1 gene and the genetic environment of blaNDM–1. Frontiers in Microbiology, 11. https://doi.org/10.3389/fmicb.2020.00700Wang, T., Zhou, Y., Zou, C., et al. (2021). Identification of a novel bla NDM variant, bla NDM-33, in an Escherichia coli isolate from hospital wastewater in China. mSphere, 6(5). https://doi.org/10.1128/msphere.00776-21Tran, V.-T., Tran, V.-H., Nguyen, D.-N., et al. (2022). The effects of one-point mutation on the New Delhi metallo beta-lactamase-1 resistance toward carbapenem antibiotics and β-lactamase inhibitors: An in silico systematic approach. International Journal of Molecular Sciences, 23(24), 16083. https://doi.org/10.3390/ijms2324160RCSB Protein Data Bank. RCSB PDB- 3ZR9: Structure of New Delhi Metallo-Beta-lactamase 1 (NDM-1) [Internet]. 2011 [cited 2023 May 28]. https://www.rcsb.org/structure/3ZR9 (accessed 2023 May 28)Zhang, G., & Hao, Q. (2011). 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03:02:39.051https://creativecommons.org/licenses/by-nc-nd/4.0/Derechos Reservados - Universidad de Santander, 2023. 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GF1dG9yKSBwYXJhIGVqZXJjZXIgZXN0b3MgZGVyZWNob3Mgc29icmUgbGEgT2JyYSB0YWwgeSBjb21vIHNlIGluZGljYSBhIGNvbnRpbnVhY2nDs246PC9wPgogICAgPG9sIHR5cGU9ImEiPgogICAgICA8bGk+UmVwcm9kdWNpciBsYSBPYnJhLCBpbmNvcnBvcmFyIGxhIE9icmEgZW4gdW5hIG8gbcOhcyBPYnJhcyBDb2xlY3RpdmFzLCB5IHJlcHJvZHVjaXIgbGEgT2JyYSBpbmNvcnBvcmFkYSBlbiBsYXMgT2JyYXMgQ29sZWN0aXZhcy48L2xpPgogICAgICA8bGk+RGlzdHJpYnVpciBjb3BpYXMgbyBmb25vZ3JhbWFzIGRlIGxhcyBPYnJhcywgZXhoaWJpcmxhcyBww7pibGljYW1lbnRlLCBlamVjdXRhcmxhcyBww7pibGljYW1lbnRlIHkvbyBwb25lcmxhcyBhIGRpc3Bvc2ljacOzbiBww7pibGljYSwgaW5jbHV5w6luZG9sYXMgY29tbyBpbmNvcnBvcmFkYXMgZW4gT2JyYXMgQ29sZWN0aXZhcywgc2Vnw7puIGNvcnJlc3BvbmRhLjwvbGk+CiAgICAgIDxsaT5EaXN0cmlidWlyIGNvcGlhcyBkZSBsYXMgT2JyYXMgRGVyaXZhZGFzIHF1ZSBzZSBnZW5lcmVuLCBleGhpYmlybGFzIHDDumJsaWNhbWVudGUsIGVqZWN1dGFybGFzIHDDumJsaWNhbWVudGUgeS9vIHBvbmVybGFzIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhLjwvbGk+CiAgICA8L29sPgogICAgPHA+TG9zIGRlcmVjaG9zIG1lbmNpb25hZG9zIGFudGVyaW9ybWVudGUgcHVlZGVuIHNlciBlamVyY2lkb3MgZW4gdG9kb3MgbG9zIG1lZGlvcyB5IGZvcm1hdG9zLCBhY3R1YWxtZW50ZSBjb25vY2lkb3MgbyBxdWUgc2UgaW52ZW50ZW4gZW4gZWwgZnV0dXJvLiBMb3MgZGVyZWNob3MgYW50ZXMgbWVuY2lvbmFkb3MgaW5jbHV5ZW4gZWwgZGVyZWNobyBhIHJlYWxpemFyIGRpY2hhcyBtb2RpZmljYWNpb25lcyBlbiBsYSBtZWRpZGEgcXVlIHNlYW4gdMOpY25pY2FtZW50ZSBuZWNlc2FyaWFzIHBhcmEgZWplcmNlciBsb3MgZGVyZWNob3MgZW4gb3RybyBtZWRpbyBvIGZvcm1hdG9zLCBwZXJvIGRlIG90cmEgbWFuZXJhIHVzdGVkIG5vIGVzdMOhIGF1dG9yaXphZG8gcGFyYSByZWFsaXphciBvYnJhcyBkZXJpdmFkYXMuIFRvZG9zIGxvcyBkZXJlY2hvcyBubyBvdG9yZ2Fkb3MgZXhwcmVzYW1lbnRlIHBvciBlbCBMaWNlbmNpYW50ZSBxdWVkYW4gcG9yIGVzdGUgbWVkaW8gcmVzZXJ2YWRvcywgaW5jbHV5ZW5kbyBwZXJvIHNpbiBsaW1pdGFyc2UgYSBhcXVlbGxvcyBxdWUgc2UgbWVuY2lvbmFuIGVuIGxhcyBzZWNjaW9uZXMgNChkKSB5IDQoZSkuPC9wPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBSZXN0cmljY2lvbmVzLgogICAgPHA+TGEgbGljZW5jaWEgb3RvcmdhZGEgZW4gbGEgYW50ZXJpb3IgU2VjY2nDs24gMyBlc3TDoSBleHByZXNhbWVudGUgc3VqZXRhIHkgbGltaXRhZGEgcG9yIGxhcyBzaWd1aWVudGVzIHJlc3RyaWNjaW9uZXM6PC9wPgogICAgPG9sIHR5cGU9ImEiPgogICAgICA8bGk+VXN0ZWQgcHVlZGUgZGlzdHJpYnVpciwgZXhoaWJpciBww7pibGljYW1lbnRlLCBlamVjdXRhciBww7pibGljYW1lbnRlLCBvIHBvbmVyIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhIGxhIE9icmEgc8OzbG8gYmFqbyBsYXMgY29uZGljaW9uZXMgZGUgZXN0YSBMaWNlbmNpYSwgeSBVc3RlZCBkZWJlIGluY2x1aXIgdW5hIGNvcGlhIGRlIGVzdGEgbGljZW5jaWEgbyBkZWwgSWRlbnRpZmljYWRvciBVbml2ZXJzYWwgZGUgUmVjdXJzb3MgZGUgbGEgbWlzbWEgY29uIGNhZGEgY29waWEgZGUgbGEgT2JyYSBxdWUgZGlzdHJpYnV5YSwgZXhoaWJhIHDDumJsaWNhbWVudGUsIGVqZWN1dGUgcMO6YmxpY2FtZW50ZSBvIHBvbmdhIGEgZGlzcG9zaWNpw7NuIHDDumJsaWNhLiBObyBlcyBwb3NpYmxlIG9mcmVjZXIgbyBpbXBvbmVyIG5pbmd1bmEgY29uZGljacOzbiBzb2JyZSBsYSBPYnJhIHF1ZSBhbHRlcmUgbyBsaW1pdGUgbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEgbyBlbCBlamVyY2ljaW8gZGUgbG9zIGRlcmVjaG9zIGRlIGxvcyBkZXN0aW5hdGFyaW9zIG90b3JnYWRvcyBlbiBlc3RlIGRvY3VtZW50by4gTm8gZXMgcG9zaWJsZSBzdWJsaWNlbmNpYXIgbGEgT2JyYS4gVXN0ZWQgZGViZSBtYW50ZW5lciBpbnRhY3RvcyB0b2RvcyBsb3MgYXZpc29zIHF1ZSBoYWdhbiByZWZlcmVuY2lhIGEgZXN0YSBMaWNlbmNpYSB5IGEgbGEgY2zDoXVzdWxhIGRlIGxpbWl0YWNpw7NuIGRlIGdhcmFudMOtYXMuIFVzdGVkIG5vIHB1ZWRlIGRpc3RyaWJ1aXIsIGV4aGliaXIgcMO6YmxpY2FtZW50ZSwgZWplY3V0YXIgcMO6YmxpY2FtZW50ZSwgbyBwb25lciBhIGRpc3Bvc2ljacOzbiBww7pibGljYSBsYSBPYnJhIGNvbiBhbGd1bmEgbWVkaWRhIHRlY25vbMOzZ2ljYSBxdWUgY29udHJvbGUgZWwgYWNjZXNvIG8gbGEgdXRpbGl6YWNpw7NuIGRlIGVsbGEgZGUgdW5hIGZvcm1hIHF1ZSBzZWEgaW5jb25zaXN0ZW50ZSBjb24gbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEuIExvIGFudGVyaW9yIHNlIGFwbGljYSBhIGxhIE9icmEgaW5jb3Jwb3JhZGEgYSB1bmEgT2JyYSBDb2xlY3RpdmEsIHBlcm8gZXN0byBubyBleGlnZSBxdWUgbGEgT2JyYSBDb2xlY3RpdmEgYXBhcnRlIGRlIGxhIG9icmEgbWlzbWEgcXVlZGUgc3VqZXRhIGEgbGFzIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEuIFNpIFVzdGVkIGNyZWEgdW5hIE9icmEgQ29sZWN0aXZhLCBwcmV2aW8gYXZpc28gZGUgY3VhbHF1aWVyIExpY2VuY2lhbnRlIGRlYmUsIGVuIGxhIG1lZGlkYSBkZSBsbyBwb3NpYmxlLCBlbGltaW5hciBkZSBsYSBPYnJhIENvbGVjdGl2YSBjdWFscXVpZXIgcmVmZXJlbmNpYSBhIGRpY2hvIExpY2VuY2lhbnRlIG8gYWwgQXV0b3IgT3JpZ2luYWwsIHNlZ8O6biBsbyBzb2xpY2l0YWRvIHBvciBlbCBMaWNlbmNpYW50ZSB5IGNvbmZvcm1lIGxvIGV4aWdlIGxhIGNsw6F1c3VsYSA0KGMpLjwvbGk+CiAgICAgIDxsaT5Vc3RlZCBubyBwdWVkZSBlamVyY2VyIG5pbmd1bm8gZGUgbG9zIGRlcmVjaG9zIHF1ZSBsZSBoYW4gc2lkbyBvdG9yZ2Fkb3MgZW4gbGEgU2VjY2nDs24gMyBwcmVjZWRlbnRlIGRlIG1vZG8gcXVlIGVzdMOpbiBwcmluY2lwYWxtZW50ZSBkZXN0aW5hZG9zIG8gZGlyZWN0YW1lbnRlIGRpcmlnaWRvcyBhIGNvbnNlZ3VpciB1biBwcm92ZWNobyBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYS4gRWwgaW50ZXJjYW1iaW8gZGUgbGEgT2JyYSBwb3Igb3RyYXMgb2JyYXMgcHJvdGVnaWRhcyBwb3IgZGVyZWNob3MgZGUgYXV0b3IsIHlhIHNlYSBhIHRyYXbDqXMgZGUgdW4gc2lzdGVtYSBwYXJhIGNvbXBhcnRpciBhcmNoaXZvcyBkaWdpdGFsZXMgKGRpZ2l0YWwgZmlsZS1zaGFyaW5nKSBvIGRlIGN1YWxxdWllciBvdHJhIG1hbmVyYSBubyBzZXLDoSBjb25zaWRlcmFkbyBjb21vIGVzdGFyIGRlc3RpbmFkbyBwcmluY2lwYWxtZW50ZSBvIGRpcmlnaWRvIGRpcmVjdGFtZW50ZSBhIGNvbnNlZ3VpciB1biBwcm92ZWNobyBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYSwgc2llbXByZSBxdWUgbm8gc2UgcmVhbGljZSB1biBwYWdvIG1lZGlhbnRlIHVuYSBjb21wZW5zYWNpw7NuIG1vbmV0YXJpYSBlbiByZWxhY2nDs24gY29uIGVsIGludGVyY2FtYmlvIGRlIG9icmFzIHByb3RlZ2lkYXMgcG9yIGVsIGRlcmVjaG8gZGUgYXV0b3IuPC9saT4KICAgICAgPGxpPlNpIHVzdGVkIGRpc3RyaWJ1eWUsIGV4aGliZSBww7pibGljYW1lbnRlLCBlamVjdXRhIHDDumJsaWNhbWVudGUgbyBlamVjdXRhIHDDumJsaWNhbWVudGUgZW4gZm9ybWEgZGlnaXRhbCBsYSBPYnJhIG8gY3VhbHF1aWVyIE9icmEgRGVyaXZhZGEgdSBPYnJhIENvbGVjdGl2YSwgVXN0ZWQgZGViZSBtYW50ZW5lciBpbnRhY3RhIHRvZGEgbGEgaW5mb3JtYWNpw7NuIGRlIGRlcmVjaG8gZGUgYXV0b3IgZGUgbGEgT2JyYSB5IHByb3BvcmNpb25hciwgZGUgZm9ybWEgcmF6b25hYmxlIHNlZ8O6biBlbCBtZWRpbyBvIG1hbmVyYSBxdWUgVXN0ZWQgZXN0w6kgdXRpbGl6YW5kbzogKGkpIGVsIG5vbWJyZSBkZWwgQXV0b3IgT3JpZ2luYWwgc2kgZXN0w6EgcHJvdmlzdG8gKG8gc2V1ZMOzbmltbywgc2kgZnVlcmUgYXBsaWNhYmxlKSwgeS9vIChpaSkgZWwgbm9tYnJlIGRlIGxhIHBhcnRlIG8gbGFzIHBhcnRlcyBxdWUgZWwgQXV0b3IgT3JpZ2luYWwgeS9vIGVsIExpY2VuY2lhbnRlIGh1YmllcmVuIGRlc2lnbmFkbyBwYXJhIGxhIGF0cmlidWNpw7NuICh2LmcuLCB1biBpbnN0aXR1dG8gcGF0cm9jaW5hZG9yLCBlZGl0b3JpYWwsIHB1YmxpY2FjacOzbikgZW4gbGEgaW5mb3JtYWNpw7NuIGRlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZWwgTGljZW5jaWFudGUsIHTDqXJtaW5vcyBkZSBzZXJ2aWNpb3MgbyBkZSBvdHJhcyBmb3JtYXMgcmF6b25hYmxlczsgZWwgdMOtdHVsbyBkZSBsYSBPYnJhIHNpIGVzdMOhIHByb3Zpc3RvOyBlbiBsYSBtZWRpZGEgZGUgbG8gcmF6b25hYmxlbWVudGUgZmFjdGlibGUgeSwgc2kgZXN0w6EgcHJvdmlzdG8sIGVsIElkZW50aWZpY2Fkb3IgVW5pZm9ybWUgZGUgUmVjdXJzb3MgKFVuaWZvcm0gUmVzb3VyY2UgSWRlbnRpZmllcikgcXVlIGVsIExpY2VuY2lhbnRlIGVzcGVjaWZpY2EgcGFyYSBzZXIgYXNvY2lhZG8gY29uIGxhIE9icmEsIHNhbHZvIHF1ZSB0YWwgVVJJIG5vIHNlIHJlZmllcmEgYSBsYSBub3RhIHNvYnJlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBvIGEgbGEgaW5mb3JtYWNpw7NuIHNvYnJlIGVsIGxpY2VuY2lhbWllbnRvIGRlIGxhIE9icmE7IHkgZW4gZWwgY2FzbyBkZSB1bmEgT2JyYSBEZXJpdmFkYSwgYXRyaWJ1aXIgZWwgY3LDqWRpdG8gaWRlbnRpZmljYW5kbyBlbCB1c28gZGUgbGEgT2JyYSBlbiBsYSBPYnJhIERlcml2YWRhICh2LmcuLCAiVHJhZHVjY2nDs24gRnJhbmNlc2EgZGUgbGEgT2JyYSBkZWwgQXV0b3IgT3JpZ2luYWwsIiBvICJHdWnDs24gQ2luZW1hdG9ncsOhZmljbyBiYXNhZG8gZW4gbGEgT2JyYSBvcmlnaW5hbCBkZWwgQXV0b3IgT3JpZ2luYWwiKS4gVGFsIGNyw6lkaXRvIHB1ZWRlIHNlciBpbXBsZW1lbnRhZG8gZGUgY3VhbHF1aWVyIGZvcm1hIHJhem9uYWJsZTsgZW4gZWwgY2Fzbywgc2luIGVtYmFyZ28sIGRlIE9icmFzIERlcml2YWRhcyB1IE9icmFzIENvbGVjdGl2YXMsIHRhbCBjcsOpZGl0byBhcGFyZWNlcsOhLCBjb21vIG3DrW5pbW8sIGRvbmRlIGFwYXJlY2UgZWwgY3LDqWRpdG8gZGUgY3VhbHF1aWVyIG90cm8gYXV0b3IgY29tcGFyYWJsZSB5IGRlIHVuYSBtYW5lcmEsIGFsIG1lbm9zLCB0YW4gZGVzdGFjYWRhIGNvbW8gZWwgY3LDqWRpdG8gZGUgb3RybyBhdXRvciBjb21wYXJhYmxlLjwvbGk+CiAgICAgIDxsaT4KICAgICAgICBQYXJhIGV2aXRhciB0b2RhIGNvbmZ1c2nDs24sIGVsIExpY2VuY2lhbnRlIGFjbGFyYSBxdWUsIGN1YW5kbyBsYSBvYnJhIGVzIHVuYSBjb21wb3NpY2nDs24gbXVzaWNhbDoKICAgICAgICA8b2wgdHlwZT0iaSI+CiAgICAgICAgICA8bGk+UmVnYWzDrWFzIHBvciBpbnRlcnByZXRhY2nDs24geSBlamVjdWNpw7NuIGJham8gbGljZW5jaWFzIGdlbmVyYWxlcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSBhdXRvcml6YXIgbGEgZWplY3VjacOzbiBww7pibGljYSBvIGxhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBkZSBsYSBvYnJhIHkgZGUgcmVjb2xlY3Rhciwgc2VhIGluZGl2aWR1YWxtZW50ZSBvIGEgdHJhdsOpcyBkZSB1bmEgc29jaWVkYWQgZGUgZ2VzdGnDs24gY29sZWN0aXZhIGRlIGRlcmVjaG9zIGRlIGF1dG9yIHkgZGVyZWNob3MgY29uZXhvcyAocG9yIGVqZW1wbG8sIFNBWUNPKSwgbGFzIHJlZ2Fsw61hcyBwb3IgbGEgZWplY3VjacOzbiBww7pibGljYSBvIHBvciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8gV2ViY2FzdCkgbGljZW5jaWFkYSBiYWpvIGxpY2VuY2lhcyBnZW5lcmFsZXMsIHNpIGxhIGludGVycHJldGFjacOzbiBvIGVqZWN1Y2nDs24gZGUgbGEgb2JyYSBlc3TDoSBwcmltb3JkaWFsbWVudGUgb3JpZW50YWRhIHBvciBvIGRpcmlnaWRhIGEgbGEgb2J0ZW5jacOzbiBkZSB1bmEgdmVudGFqYSBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYS48L2xpPgogICAgICAgICAgPGxpPlJlZ2Fsw61hcyBwb3IgRm9ub2dyYW1hcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSByZWNvbGVjdGFyLCBpbmRpdmlkdWFsbWVudGUgbyBhIHRyYXbDqXMgZGUgdW5hIHNvY2llZGFkIGRlIGdlc3Rpw7NuIGNvbGVjdGl2YSBkZSBkZXJlY2hvcyBkZSBhdXRvciB5IGRlcmVjaG9zIGNvbmV4b3MgKHBvciBlamVtcGxvLCBsb3MgY29uc2FncmFkb3MgcG9yIGxhIFNBWUNPKSwgdW5hIGFnZW5jaWEgZGUgZGVyZWNob3MgbXVzaWNhbGVzIG8gYWxnw7puIGFnZW50ZSBkZXNpZ25hZG8sIGxhcyByZWdhbMOtYXMgcG9yIGN1YWxxdWllciBmb25vZ3JhbWEgcXVlIFVzdGVkIGNyZWUgYSBwYXJ0aXIgZGUgbGEgb2JyYSAo4oCcdmVyc2nDs24gY292ZXLigJ0pIHkgZGlzdHJpYnV5YSwgZW4gbG9zIHTDqXJtaW5vcyBkZWwgcsOpZ2ltZW4gZGUgZGVyZWNob3MgZGUgYXV0b3IsIHNpIGxhIGNyZWFjacOzbiBvIGRpc3RyaWJ1Y2nDs24gZGUgZXNhIHZlcnNpw7NuIGNvdmVyIGVzdMOhIHByaW1vcmRpYWxtZW50ZSBkZXN0aW5hZGEgbyBkaXJpZ2lkYSBhIG9idGVuZXIgdW5hIHZlbnRhamEgY29tZXJjaWFsIG8gdW5hIGNvbXBlbnNhY2nDs24gbW9uZXRhcmlhIHByaXZhZGEuPC9saT4KICAgICAgICA8L29sPgogICAgICA8L2xpPgogICAgICA8bGk+R2VzdGnDs24gZGUgRGVyZWNob3MgZGUgQXV0b3Igc29icmUgSW50ZXJwcmV0YWNpb25lcyB5IEVqZWN1Y2lvbmVzIERpZ2l0YWxlcyAoV2ViQ2FzdGluZykuIFBhcmEgZXZpdGFyIHRvZGEgY29uZnVzacOzbiwgZWwgTGljZW5jaWFudGUgYWNsYXJhIHF1ZSwgY3VhbmRvIGxhIG9icmEgc2VhIHVuIGZvbm9ncmFtYSwgZWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSBhdXRvcml6YXIgbGEgZWplY3VjacOzbiBww7pibGljYSBkaWdpdGFsIGRlIGxhIG9icmEgKHBvciBlamVtcGxvLCB3ZWJjYXN0KSB5IGRlIHJlY29sZWN0YXIsIGluZGl2aWR1YWxtZW50ZSBvIGEgdHJhdsOpcyBkZSB1bmEgc29jaWVkYWQgZGUgZ2VzdGnDs24gY29sZWN0aXZhIGRlIGRlcmVjaG9zIGRlIGF1dG9yIHkgZGVyZWNob3MgY29uZXhvcyAocG9yIGVqZW1wbG8sIEFDSU5QUk8pLCBsYXMgcmVnYWzDrWFzIHBvciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8sIHdlYmNhc3QpLCBzdWpldGEgYSBsYXMgZGlzcG9zaWNpb25lcyBhcGxpY2FibGVzIGRlbCByw6lnaW1lbiBkZSBEZXJlY2hvIGRlIEF1dG9yLCBzaSBlc3RhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBlc3TDoSBwcmltb3JkaWFsbWVudGUgZGlyaWdpZGEgYSBvYnRlbmVyIHVuYSB2ZW50YWphIGNvbWVyY2lhbCBvIHVuYSBjb21wZW5zYWNpw7NuIG1vbmV0YXJpYSBwcml2YWRhLjwvbGk+CiAgICA8L29sPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBSZXByZXNlbnRhY2lvbmVzLCBHYXJhbnTDrWFzIHkgTGltaXRhY2lvbmVzIGRlIFJlc3BvbnNhYmlsaWRhZC4KICAgIDxwPkEgTUVOT1MgUVVFIExBUyBQQVJURVMgTE8gQUNPUkRBUkFOIERFIE9UUkEgRk9STUEgUE9SIEVTQ1JJVE8sIEVMIExJQ0VOQ0lBTlRFIE9GUkVDRSBMQSBPQlJBIChFTiBFTCBFU1RBRE8gRU4gRUwgUVVFIFNFIEVOQ1VFTlRSQSkg4oCcVEFMIENVQUzigJ0sIFNJTiBCUklOREFSIEdBUkFOVMONQVMgREUgQ0xBU0UgQUxHVU5BIFJFU1BFQ1RPIERFIExBIE9CUkEsIFlBIFNFQSBFWFBSRVNBLCBJTVBMw41DSVRBLCBMRUdBTCBPIENVQUxRVUlFUkEgT1RSQSwgSU5DTFVZRU5ETywgU0lOIExJTUlUQVJTRSBBIEVMTEFTLCBHQVJBTlTDjUFTIERFIFRJVFVMQVJJREFELCBDT01FUkNJQUJJTElEQUQsIEFEQVBUQUJJTElEQUQgTyBBREVDVUFDScOTTiBBIFBST1DDk1NJVE8gREVURVJNSU5BRE8sIEFVU0VOQ0lBIERFIElORlJBQ0NJw5NOLCBERSBBVVNFTkNJQSBERSBERUZFQ1RPUyBMQVRFTlRFUyBPIERFIE9UUk8gVElQTywgTyBMQSBQUkVTRU5DSUEgTyBBVVNFTkNJQSBERSBFUlJPUkVTLCBTRUFOIE8gTk8gREVTQ1VCUklCTEVTIChQVUVEQU4gTyBOTyBTRVIgRVNUT1MgREVTQ1VCSUVSVE9TKS4gQUxHVU5BUyBKVVJJU0RJQ0NJT05FUyBOTyBQRVJNSVRFTiBMQSBFWENMVVNJw5NOIERFIEdBUkFOVMONQVMgSU1QTMONQ0lUQVMsIEVOIENVWU8gQ0FTTyBFU1RBIEVYQ0xVU0nDk04gUFVFREUgTk8gQVBMSUNBUlNFIEEgVVNURUQuPC9wPgogIDwvbGk+CiAgPGJyLz4KICA8bGk+CiAgICBMaW1pdGFjacOzbiBkZSByZXNwb25zYWJpbGlkYWQuCiAgICA8cD5BIE1FTk9TIFFVRSBMTyBFWElKQSBFWFBSRVNBTUVOVEUgTEEgTEVZIEFQTElDQUJMRSwgRUwgTElDRU5DSUFOVEUgTk8gU0VSw4EgUkVTUE9OU0FCTEUgQU5URSBVU1RFRCBQT1IgREHDkU8gQUxHVU5PLCBTRUEgUE9SIFJFU1BPTlNBQklMSURBRCBFWFRSQUNPTlRSQUNUVUFMLCBQUkVDT05UUkFDVFVBTCBPIENPTlRSQUNUVUFMLCBPQkpFVElWQSBPIFNVQkpFVElWQSwgU0UgVFJBVEUgREUgREHDkU9TIE1PUkFMRVMgTyBQQVRSSU1PTklBTEVTLCBESVJFQ1RPUyBPIElORElSRUNUT1MsIFBSRVZJU1RPUyBPIElNUFJFVklTVE9TIFBST0RVQ0lET1MgUE9SIEVMIFVTTyBERSBFU1RBIExJQ0VOQ0lBIE8gREUgTEEgT0JSQSwgQVVOIENVQU5ETyBFTCBMSUNFTkNJQU5URSBIQVlBIFNJRE8gQURWRVJUSURPIERFIExBIFBPU0lCSUxJREFEIERFIERJQ0hPUyBEQcORT1MuIEFMR1VOQVMgTEVZRVMgTk8gUEVSTUlURU4gTEEgRVhDTFVTScOTTiBERSBDSUVSVEEgUkVTUE9OU0FCSUxJREFELCBFTiBDVVlPIENBU08gRVNUQSBFWENMVVNJw5NOIFBVRURFIE5PIEFQTElDQVJTRSBBIFVTVEVELjwvcD4KICA8L2xpPgogIDxici8+CiAgPGxpPgogICAgVMOpcm1pbm8uCiAgICA8b2wgdHlwZT0iYSI+CiAgICAgIDxsaT5Fc3RhIExpY2VuY2lhIHkgbG9zIGRlcmVjaG9zIG90b3JnYWRvcyBlbiB2aXJ0dWQgZGUgZWxsYSB0ZXJtaW5hcsOhbiBhdXRvbcOhdGljYW1lbnRlIHNpIFVzdGVkIGluZnJpbmdlIGFsZ3VuYSBjb25kaWNpw7NuIGVzdGFibGVjaWRhIGVuIGVsbGEuIFNpbiBlbWJhcmdvLCBsb3MgaW5kaXZpZHVvcyBvIGVudGlkYWRlcyBxdWUgaGFuIHJlY2liaWRvIE9icmFzIERlcml2YWRhcyBvIENvbGVjdGl2YXMgZGUgVXN0ZWQgZGUgY29uZm9ybWlkYWQgY29uIGVzdGEgTGljZW5jaWEsIG5vIHZlcsOhbiB0ZXJtaW5hZGFzIHN1cyBsaWNlbmNpYXMsIHNpZW1wcmUgcXVlIGVzdG9zIGluZGl2aWR1b3MgbyBlbnRpZGFkZXMgc2lnYW4gY3VtcGxpZW5kbyDDrW50ZWdyYW1lbnRlIGxhcyBjb25kaWNpb25lcyBkZSBlc3RhcyBsaWNlbmNpYXMuIExhcyBTZWNjaW9uZXMgMSwgMiwgNSwgNiwgNywgeSA4IHN1YnNpc3RpcsOhbiBhIGN1YWxxdWllciB0ZXJtaW5hY2nDs24gZGUgZXN0YSBMaWNlbmNpYS48L2xpPgogICAgICA8bGk+U3VqZXRhIGEgbGFzIGNvbmRpY2lvbmVzIHkgdMOpcm1pbm9zIGFudGVyaW9yZXMsIGxhIGxpY2VuY2lhIG90b3JnYWRhIGFxdcOtIGVzIHBlcnBldHVhIChkdXJhbnRlIGVsIHBlcsOtb2RvIGRlIHZpZ2VuY2lhIGRlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZSBsYSBvYnJhKS4gTm8gb2JzdGFudGUgbG8gYW50ZXJpb3IsIGVsIExpY2VuY2lhbnRlIHNlIHJlc2VydmEgZWwgZGVyZWNobyBhIHB1YmxpY2FyIHkvbyBlc3RyZW5hciBsYSBPYnJhIGJham8gY29uZGljaW9uZXMgZGUgbGljZW5jaWEgZGlmZXJlbnRlcyBvIGEgZGVqYXIgZGUgZGlzdHJpYnVpcmxhIGVuIGxvcyB0w6lybWlub3MgZGUgZXN0YSBMaWNlbmNpYSBlbiBjdWFscXVpZXIgbW9tZW50bzsgZW4gZWwgZW50ZW5kaWRvLCBzaW4gZW1iYXJnbywgcXVlIGVzYSBlbGVjY2nDs24gbm8gc2Vydmlyw6EgcGFyYSByZXZvY2FyIGVzdGEgbGljZW5jaWEgbyBxdWUgZGViYSBzZXIgb3RvcmdhZGEgLCBiYWpvIGxvcyB0w6lybWlub3MgZGUgZXN0YSBsaWNlbmNpYSksIHkgZXN0YSBsaWNlbmNpYSBjb250aW51YXLDoSBlbiBwbGVubyB2aWdvciB5IGVmZWN0byBhIG1lbm9zIHF1ZSBzZWEgdGVybWluYWRhIGNvbW8gc2UgZXhwcmVzYSBhdHLDoXMuIExhIExpY2VuY2lhIHJldm9jYWRhIGNvbnRpbnVhcsOhIHNpZW5kbyBwbGVuYW1lbnRlIHZpZ2VudGUgeSBlZmVjdGl2YSBzaSBubyBzZSBsZSBkYSB0w6lybWlubyBlbiBsYXMgY29uZGljaW9uZXMgaW5kaWNhZGFzIGFudGVyaW9ybWVudGUuPC9saT4KICAgIDwvb2w+CiAgPC9saT4KICA8YnIvPgogIDxsaT4KICAgIFZhcmlvcy4KICAgIDxvbCB0eXBlPSJhIj4KICAgICAgPGxpPkNhZGEgdmV6IHF1ZSBVc3RlZCBkaXN0cmlidXlhIG8gcG9uZ2EgYSBkaXNwb3NpY2nDs24gcMO6YmxpY2EgbGEgT2JyYSBvIHVuYSBPYnJhIENvbGVjdGl2YSwgZWwgTGljZW5jaWFudGUgb2ZyZWNlcsOhIGFsIGRlc3RpbmF0YXJpbyB1bmEgbGljZW5jaWEgZW4gbG9zIG1pc21vcyB0w6lybWlub3MgeSBjb25kaWNpb25lcyBxdWUgbGEgbGljZW5jaWEgb3RvcmdhZGEgYSBVc3RlZCBiYWpvIGVzdGEgTGljZW5jaWEuPC9saT4KICAgICAgPGxpPlNpIGFsZ3VuYSBkaXNwb3NpY2nDs24gZGUgZXN0YSBMaWNlbmNpYSByZXN1bHRhIGludmFsaWRhZGEgbyBubyBleGlnaWJsZSwgc2Vnw7puIGxhIGxlZ2lzbGFjacOzbiB2aWdlbnRlLCBlc3RvIG5vIGFmZWN0YXLDoSBuaSBsYSB2YWxpZGV6IG5pIGxhIGFwbGljYWJpbGlkYWQgZGVsIHJlc3RvIGRlIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEgeSwgc2luIGFjY2nDs24gYWRpY2lvbmFsIHBvciBwYXJ0ZSBkZSBsb3Mgc3VqZXRvcyBkZSBlc3RlIGFjdWVyZG8sIGFxdcOpbGxhIHNlIGVudGVuZGVyw6EgcmVmb3JtYWRhIGxvIG3DrW5pbW8gbmVjZXNhcmlvIHBhcmEgaGFjZXIgcXVlIGRpY2hhIGRpc3Bvc2ljacOzbiBzZWEgdsOhbGlkYSB5IGV4aWdpYmxlLjwvbGk+CiAgICAgIDxsaT5OaW5nw7puIHTDqXJtaW5vIG8gZGlzcG9zaWNpw7NuIGRlIGVzdGEgTGljZW5jaWEgc2UgZXN0aW1hcsOhIHJlbnVuY2lhZGEgeSBuaW5ndW5hIHZpb2xhY2nDs24gZGUgZWxsYSBzZXLDoSBjb25zZW50aWRhIGEgbWVub3MgcXVlIGVzYSByZW51bmNpYSBvIGNvbnNlbnRpbWllbnRvIHNlYSBvdG9yZ2FkbyBwb3IgZXNjcml0byB5IGZpcm1hZG8gcG9yIGxhIHBhcnRlIHF1ZSByZW51bmNpZSBvIGNvbnNpZW50YS48L2xpPgogICAgICA8bGk+RXN0YSBMaWNlbmNpYSByZWZsZWphIGVsIGFjdWVyZG8gcGxlbm8gZW50cmUgbGFzIHBhcnRlcyByZXNwZWN0byBhIGxhIE9icmEgYXF1w60gbGljZW5jaWFkYS4gTm8gaGF5IGFycmVnbG9zLCBhY3VlcmRvcyBvIGRlY2xhcmFjaW9uZXMgcmVzcGVjdG8gYSBsYSBPYnJhIHF1ZSBubyBlc3TDqW4gZXNwZWNpZmljYWRvcyBlbiBlc3RlIGRvY3VtZW50by4gRWwgTGljZW5jaWFudGUgbm8gc2UgdmVyw6EgbGltaXRhZG8gcG9yIG5pbmd1bmEgZGlzcG9zaWNpw7NuIGFkaWNpb25hbCBxdWUgcHVlZGEgc3VyZ2lyIGVuIGFsZ3VuYSBjb211bmljYWNpw7NuIGVtYW5hZGEgZGUgVXN0ZWQuIEVzdGEgTGljZW5jaWEgbm8gcHVlZGUgc2VyIG1vZGlmaWNhZGEgc2luIGVsIGNvbnNlbnRpbWllbnRvIG11dHVvIHBvciBlc2NyaXRvIGRlbCBMaWNlbmNpYW50ZSB5IFVzdGVkLjwvbGk+CiAgICA8L29sPgogIDwvbGk+CiAgPGJyLz4KPC9vbD4K 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