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Investigación
Bacterial Genetics
Líneas de investigación
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Bacterial Genetics
Our group has been studying for more than 30 years the mechanisms of antibiotic resistance in Streptococcus pneumoniae (Spn). Our objectives are to understand the molecular basis of antimicrobial action, to search for new targets of action and new compounds. Seconeolitsine (SCN) is one of these new compounds targeting topoisomerase I (Topo I). As for the search for new targets, our research has focused in recent years on the factors that organize the topology of the chromosome, allowing optimal compaction (about 1000-fold) to harmonize its replication, chromosome segregation and gene expression. This compaction is mediated both by the level of DNA supercoiling (Sc) and by association with nucleoid-binding proteins (NAPs). The level of Sc depends mainly on the enzymatic activities of their DNA topoisomerases, reaching a homeostatic equilibrium by the opposite activities of the topoisomerases that relax DNA (Topo I and Topo IV), and of gyrase, which introduces negative Sc. Our group has characterized the three Spn topoisomerases and two NAPs: HU and SatR. In addition, the availability of antimicrobials that inhibit each of the Spn topoisomerases has allowed us to analyze their transcriptome under conditions of local or global change of the Sc level and to define gene domains of coordinated transcription and similar functions. Fluoroquinolones, which inhibit Topo IV and gyrase, produce local changes in Sc that induce alterations in 6% of the transcriptome, altering metabolic pathways that originate an increase in reactive oxygen species (ROS) that contribute to lethality, in accordance with the general mechanism of bactericidal antibiotics. On the other hand, the induction of global changes in Sc by novobiocin (NOV, gyrase inhibitor), or by SCN (Topo I inhibitor), has allowed us to define topological domains. Global changes in Sc include the regulation of topoisomerase genes: its decrease activates the transcription of gyrase genes (gyrA, gyrB) and inhibits those of Topo IV (parEC) and Topo I (topA); the increase in Sc regulates the expression of topA. Decreased Sc affects 37% of the genome, with >68% of genes clustered in 15 domains. Increased Sc affects 10% of the genome, with 25% of the genes clustered in 12 domains. The AT content in the genome correlates with the domains, being higher in UP domains than in DOWN domains. The genes in the different domains have common functional characteristics, indicating that they have been subjected to topological selective pressure to determine the location of genes involved in metabolism, virulence and competition.
The current objectives of the group are:
1. Identification of factors that stabilize chromosome topology: NAPs, ncRNAs, intra-chromosomal interactions.
2. Regulation of transcription in response to topological stress: in vivo localization of DNA topoisomerases, RNA polymerase and NAPs.
3. Topo I as a new antimicrobial target and action of SCN.
4. Design of antisense RNAs and use of the CRISPR system as new antibacterial agents.
Proyectos de investigación
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1) Project Title: Interaction Between DNA Supercoiling and Transcription in the Human Pathogen Streptococcus pneumoniae.
Principal Investigator: Adela González de la Campa
Funding Entity: Ministry of Science and Innovation, State Research Agency (Call for "R&D&I Projects" 2020 – "Research Challenges" and "Knowledge Generation" Modalities).
Reference: PID2021-124738OB-100.
Duration: 2022-2025.
Funding Amount: €108,900.
2) Project Title: Study of the Factors Organizing the Chromosome of Streptococcus pneumoniae: New Antibiotic Targets and Resistance Mechanisms.
Principal Investigator: Adela González de la Campa
Funding Entity: Ministry of Economy, Industry, and Competitiveness. State Research Agency.
Reference: BIO2017-82951-R.
Duration: 2018-2020.
Funding Amount: €169,400.
3) Project Title: Role of DNA Topoisomerases and Nucleoid-Associated Proteins in the Chromosome Organization of Streptococcus pneumoniae: Response to Antibiotics and Virulence.
Principal Investigator: Adela González de la Campa
Funding Entity: Ministry of Economy and Competitiveness. Secretariat of State for Research, Development, and Innovation.
Reference: BIO2014-55462.
Duration: 2015-2017.
Funding Amount: €193,600.
4) Project Title: The Control of Supercoiling Level in Streptococcus pneumoniae as an Antimicrobial Target.
Principal Investigator: Adela González de la Campa
Funding Entity: Ministry of Economy and Competitiveness. Secretariat of State for Research, Development, and Innovation.
Reference: BIO2011-25343.
Duration: 2012-2015.
Funding Amount: €209,000.
5) Project Title: Role of Small Non-Coding RNAs in the Pathogenicity of Streptococcus pneumoniae.
Principal Investigator: Mónica Amblar Esteban
Funding Entity: Ministry of Economy and Competitiveness. Strategic Health Action (AES).
Reference: PI11/00656.
Duration: 2012-2015.
Funding Amount: €198,714.
Publicaciones destacadas
Arbovirus surveillance: first dengue virus detection in local Aedes albopictus mosquitoes in Europe, Catalonia, Spain, 2015.
1. C Aranda; MJ Martínez; T Montalvo; R Eritja; J Navero-Castillejos; E Herreros; E Marqués; R Escosa; I Corbella; E Bigas; L Picart; M Jané; I Barrabeig; N Torner; S Talavera; Ana Vázquez; María Paz Sánchez-Seco; Nuria Busquets. Arbovirus surveillance: first dengue virus detection in local Aedes albopictus mosquitoes in Europe, Catalonia, Spain, 2015.Eurosurveillance. 23 - 47, 2018.
PUBMED DOIPhylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus, Spain
2. Eva Ramírez de Arellano; Lourdes Hernández; M José Goyanes; Marta Arsuaga; Ana Fernández Cruz; Anabel Negredo; María Paz Sánchez Seco. Phylogenetic Characterization of Crimean-Congo Hemorrhagic Fever Virus, Spain. Emerging infectious diseases. 23 - 12, pp. 2078 - 2080. 12/2017. ISSN 1080-6059
PUBMED DOIToscana virus infection in Catalonia (Spain).
4. Neus Cardeñosa; Diana Kaptoul; Pedro Fernández Viladrich; Carles Aranda; Fernando de Ory; Jordi Niubó; Pere Plans; Angela Domínguez; Giovanni Fedele; Antonio Tenorio; María Paz Sánchez Seco. Toscana virus infection in Catalonia (Spain). Vector borne and zoonotic diseases (Larchmont, N.Y.). 13 - 4, pp. 273 - 278. 04/2013. ISSN 1557-7759
PUBMED DOI. Autochthonous Crimean-Congo Hemorrhagic Fever in Spain
5. Anabel Negredo; Fernando de la Calle Prieto; Eduardo Palencia Herrejón; Marta Mora Rillo; Jenaro Astray Mochales; María P Sánchez Seco; Esther Bermejo Lopez; Javier Menárguez; Ana Fernández Cruz; Beatriz Sánchez Artola; Elena Keough Delgado; Eva Ramírez de Arellano; Fátima Lasala; Jakob Milla; Jose L Fraile; Maria Ordobás Gavín; Amalia Martinez de la Gándara; Lorenzo López Perez; Domingo Diaz Diaz; M Aurora López García; Pilar Delgado Jimenez; Alejandro Martín Quirós; Elena Trigo; Juan C Figueira; Jesús Manzanares; Elena Rodriguez Baena; Luis Garcia Comas; Olaia Rodríguez Fraga; Nicolás García Arenzana; Maria V Fernández Díaz; Victor M Cornejo; Petra Emmerich; Jonas Schmidt Chanasit; Jose R Arribas. Autochthonous Crimean-Congo Hemorrhagic Fever in Spain.The New England journal of medicine. 377 - 2, pp. 154 - 161. 13/07/2017. ISSN 1533-4406
PUBMED DOIZika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games
6. Natalia Rodriguez Valero; Alberto M Borobia; Mar Lago; Maria Paz Sánchez Seco; Fernando de Ory; Ana Vázquez; Jose Luis Pérez Arellano; Cristina Carranza Rodríguez; Miguel J Martínez; Alicia Capón; Elias Cañas; Joaquin Salas Coronas; Arkaitz Azcune Galparsoro; Jose Muñoz. Zika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games. Emerging infectious diseases. 23 - 8, pp. 1426 - 1428. 08/2017. ISSN 1080-6059
PUBMED DOIProlonged Zika Virus Viremia during Pregnancy
7. Anna Suy; Elena Sulleiro; Carlota Rodó; Élida Vázquez; Cristina Bocanegra; Israel Molina; Juliana Esperalba; María P Sánchez Seco; Hector Boix; Tomás Pumarola; Elena Carreras. Prolonged Zika Virus Viremia during Pregnancy. The New England journal of medicine. 375 - 26, pp. 2611 - 2613. 29/12/2016. ISSN 1533-4406
PUBMED DOIRibavirin Had Demonstrable Effects on the Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Population and Load in a Patient With CCHF Infection
9. Nicole Espy; Unai Pérez-Sautu; Eva Ramírez de Arellano; Anabel Negredo; MR Wiley; S Bavari; Marta Díaz Manéndez; María Paz Sánchez-Seco; Gustavo Palacios. Ribavirin Had Demonstrable Effects on the Crimean-Congo Hemorrhagic Fever Virus (CCHFV) Population and Load in a Patient With CCHF Infection. J Infect Dis. 217 - 12, pp. 1952 - 1956. 25/05/2018.
PUBMED DOIContent with Investigacion .
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Adela González de la Campa
Scientific Investigator
ORCID code: 0000-0002-3598-2548
Dr. Adela González de la Campa obtained her degree in Biology in 1981 and her PhD in 1985 from the Complutense University of Madrid. She did her doctoral thesis in the laboratory of Dr. Miguel Vicente at the Centro de Investigaciones Biológicas of CSIC. Subsequently she worked for 2 years at Brookhaven National Laboratory, Upton, New York, USA in the laboratory of Sandford Lacks. After this postdoctoral stage in the USA, she worked for 3 years as a Reincorporation Fellow at the Centro de Investigaciones Biológicas of CSIC in the laboratory of Dr. Manuel Espinosa. He is a CSIC Senior Scientist since 1990 and Research Scientist since 2007. He participated as group leader of the CIBER of Respiratory Diseases (CIBERES) from 2007 to 2015. Since 1990, she has been the principal investigator of the Bacterial Genetics Unit at the National Centre for Microbiology.
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María José Ferrándiz Avellano
Research Scientist
ORCID code: 0000-0003-1428-9506
Dr. María José Ferrández obtained her degree in Biology in 1990 and her PhD in 1997 from the Complutense University of Madrid. She completed her doctoral thesis at the Centro de Investigaciones Biológicas of CSIC in the laboratory of Dr. Miguel Vicente. She completed her postdoctoral training at the Centro Nacional de Microbiología of Instituto de Salud Carlos III (1998-2001 and 2003-2006) and at the Institute of Infection and Immunity (University of Nottingham) from 2001- 2003. From 2007 to 2015, she participated as a researcher of the CIBER of Respiratory Diseases (CIBERES). Since 2006, she is a Full Scientist at the National Microbiology Center of the ISCIII.
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Mónica Amblar Esteban
Research Scientist
ORCID code: 0000-0003-3530-615X
Dr. Mónica Amblar obtained her degree in Biology in 1993 and her PhD in 2000 from the Complutense University of Madrid. She did her doctoral thesis in the laboratory of Dr. Paloma López at the Centro de Investigaciones Biológicas of CSIC. Subsequently, she worked for 5 and half years at the Instituto de Tecnología Química e Biológica/Universidade Nova de Lisboa, Oeiras (Portugal) in the laboratory of Prof. Cecilia M. Arraiano. After this postdoctoral stage he rejoined the Centro de Investigaciones Biológicas del CSIC where he worked for 2 years as a Postdoctoral Researcher in the laboratory of Dr. Paloma López. Subsequently, he joined the National Microbiology Center of the ISCIII with a Ramón y Cajal contract and in 2010 he obtained a position as a Full Scientist at the same center.
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Noelia Martínez Montes
FP2 Technician
Technician in Clinical and Biomedical Laboratory from IES Moratalaz in 2019. Worked for 10 months as a Technician in the Emergency Laboratory at Reina Sofía University Hospital and for 1 year and 9 months in various laboratories at La Paz University Hospital. Since March 2023, has been working in our laboratory at the National Center for Microbiology of ISCIII under a Laboratory Technician contract within the Youth Guarantee Plan of the Community of Madrid.
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Laura Alfonso Alarcón
PhD student
ORCID code: 0000-0003-1560-1100
Degree in Biochemistry in 2020 from National University of Asunción (Paraguay). Master in Microbiology and Health in 2024 from Pais Vasco University (Spain). Stays in Paraguay in Instituto de Investigaciones en Ciencias de la Salud; Facultad de Ciencias Químicas and Hospital Nacional de Itaugua. She is actually a predoctoral student of the Microbiología y Parasitología program of Complutense University of Madrid, with a “Don Carlos Antonio López” (BECAL) fellowship from Paraguay Goverment.
List of staff
Información adicional
Streptococcus pneumoniae is a human pathogen that, despite the development of vaccines, continues to be an important cause of mortality and morbidity. We investigate the mechanisms of antibiotic resistance in this bacterium. On the one hand by identifying new therapeutic targets and on the other hand by investigating the molecular basis of the action of antibiotics already used in clinical practice (the fluoroquinolones levofloxacin and moxifloxacin) or not yet used (seconeolitsine). For this purpose, we used a multidisciplinary analysis involving genomics, transcriptomics and proteomics to understand the organization of the S. pneumoniae chromosome and the identification of the factors that stabilize this organization, including ncRNAs. Changes in the level of global supercoiling, either by inhibition of gyrase (decrease) or by inhibition of topoisomerase I (increase) alter the transcriptome. The modulated genes are located in domains, whose genes show specific functional characteristics. The aim is to identify new factors essential for S. pneumoniae physiology and to characterize transcriptional regulation in response to topological stress. In addition, RNA interference technology and CRISPR systems will be used as novel antibacterials. These studies will establish the bases for translational research aimed at the development of new therapeutic targets for the treatment of pneumococcal diseases.
Streptococcus pneumoniae is a human pathogen that, despite the development of vaccines, continues to be an important cause of mortality and morbidity. We investigate the mechanisms of antibiotic resistance in this bacterium. On the one hand by identifying new therapeutic targets and on the other hand by investigating the molecular basis of the action of antibiotics already used in clinical practice (the fluoroquinolones levofloxacin and moxifloxacin) or not yet used (seconeolitsine). For this purpose, we used a multidisciplinary analysis involving genomics, transcriptomics and proteomics to understand the organization of the S. pneumoniae chromosome and the identification of the factors that stabilize this organization, including ncRNAs. Changes in the level of global supercoiling, either by inhibition of gyrase (decrease) or by inhibition of topoisomerase I (increase) alter the transcriptome. The modulated genes are located in domains, whose genes show specific functional characteristics. The aim is to identify new factors essential for S. pneumoniae physiology and to characterize transcriptional regulation in response to topological stress. In addition, RNA interference technology and CRISPR systems will be used as novel antibacterials. These studies will establish the bases for translational research aimed at the development of new therapeutic targets for the treatment of pneumococcal diseases.