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Molecular bases of antimicrobial action in streptococci

Specialized Group:

Adela González de la Campa

Bacterial Genetics Unit, National Microbiology Center, Carlos III Health Institute, Crtra Majadahonda-Pozuelo Km 2, 28220 Madrid

agcampa@isciii.es

agcampa@isciii.es agcampa@isciii.es

agcampa@isciii.es Streptococcus pneumoniae agcampa@isciii.es in vivo of resistance during antibiotic treatment), including both antimicrobials used for diagnosis (optochin) and others used in the treatment of infections (mainly the fluoroquinolones levofloxacin and moxifloxacin), or not yet used, such as seconeolitsine. The objectives of the group are to know the molecular bases of the action of antimicrobials as well as to search for new compounds and new targets of action. The group is currently made up of a Scientific Researcher from the CSIC (Adela González de la Campa), two Senior Scientists from the ISCIII (Maria José Ferrándiz and Mónica Amblar), a contracted doctoral professor from the UCM (Maria Teresa García), a contracted predoctoral ( Miriam García López) and a TFG student (Patricia Rabanal).

In the last ten years we have focused on the study of the topological organization of the SPN chromosome, a fundamental aspect for the development of new antimicrobials and for the improvement of antibiotic treatment. The chromosome presents an optimal compaction (up to 1000-fold) to harmonize its replication, chromosomal segregation and gene expression. This compaction is mediated both by the level of DNA supercoiling (SC) and by the association of nucleoid-binding proteins (NAPs). The level of SC in SPN depends mainly on the enzymatic activities of its DNA topoisomerases, with a homeostatic equilibrium being achieved by the opposing activities of topoisomerases that relax DNA (topoisomerases I and IV), and gyrase, which introduces negative SC. Fluoroquinolones (FQs) inhibit gyrase and Topo IV by forming an enzyme-DNA-FQ ternary complex that produces double-strand breaks. Resistance to FQs is mainly caused by the alteration of its molecular targets, either by point mutation or by intraspecific or interspecific horizontal transfer with commensal streptococci. The expulsion of FQs out of the cell also plays a role in resistance in SPNs. We have shown that alterations in a stem-loop type structure located in the 3' position of patAB, which encodes an ABC-type transporter, confer increased expression of these genes and increased resistance to FQs.

, which encodes an ABC-type transporter, confer increased expression of these genes and increased resistance to FQs. Escherichia coli), rich in AT (60%), and encodes very few NAPs. We have characterized the HU protein, the only classic NAP described in SPN, which contributes to chromosome compaction. The chromosome is organized into several levels of compaction according to the size of the units that constitute them: macrodomains (megabase range) and SC domains (Kb range, isolated loops). The availability of drugs that inhibit each of the SPN topoisomerases has allowed us to analyze the SPN transcriptome under conditions of local or global change in the SC level and define SC domains whose genes present coordinated transcription and similar functions. CFs produce local changes in the CS that induce alterations in the transcriptome that affect 5.2% (levofloxacin) and 6.5% (moxifloxacin) of the genome. Both FQs, by regulating the transcription of different metabolic pathways, produce an increase in reactive oxygen species (ROS) that contribute to lethality, in accordance with the general model of action of bactericidal antibiotics. These ROS are essential in the post-antibiotic effect of FQs. On the other hand, the induction of global changes in SC by novobiocin (GyrB inhibitor), or by seconeolitsina (Topo I inhibitor), has allowed us to define SC domains. The global changes of the SC include the regulation of its topoisomerase genes: its decrease activates the transcription of the gyrase genes (gyrA, gyrB) and inhibits those of Topo IV (parEC) and inhibits those of Topo IV (topA) and inhibits those of Topo IV ( topA) and inhibits those of Topo IV ( >68% of genes clustered in 15 domains. The increase in SC affects 10% of the genome, with 25% of the genes grouped into 12 domains. The domains defined in these opposite situations mostly overlap, indicating that the chromosome is organized in SC domains with fixed location. According to its response to SC decrease, the SPN chromosome is organized into 5 types of domains: activated (UP), inhibited (DOWN), unregulated with conserved position (pcNR), unregulated with variable position (pvNR), and rich. in AT(ATr). The AT content in the genome correlates with the domains, being higher in the UP domains than in the DOWN ones. The ATr domains contain the least transcribed genes and could have a structural function. The genes of the different domains show specific functional characteristics, which suggests that they have been subjected to topological selective pressure that has led to defining the location of genes involved in metabolism, virulence and competition.

Regarding the regulation of the SC, the transcription of gyrB and topA Regarding the regulation of the SC, the transcription of topA in a DOWN domain and gyrB Regarding the regulation of the SC, the transcription of parEC and of gyrA Regarding the regulation of the SC, the transcription of gyrA has an intrinsic curvature that acts as an activator per se Regarding the regulation of the SC, the transcription of gyrARegarding the regulation of the SC, the transcription of gyrA.

Representative bibliography

  1. Regarding the regulation of the SC, the transcription of Regarding the regulation of the SC, the transcription of Streptococcus pneumoniae. Antimicrob Agents Chemother. 58:247-257.
  2. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257.. . Antimicrob Agents Chemother. 58:247-257..
  3. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257.
  4. . Antimicrob Agents Chemother. 58:247-257. AG. . Antimicrob Agents Chemother. 58:247-257. Streptococcus pneumoniae. . Antimicrob Agents Chemother. 58:247-257. . Antimicrob Agents Chemother. 58:247-257.. Antimicrob Agents Chemother. 58:247-257.
  5. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. (Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.
  6. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. Streptococcus pneumoniae Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.
  7. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. Streptococcus pneumoniaeFerrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.. Assay validationFerrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG.
  8. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. . Antimicrob Agents Chemother. 58:247-257. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. Streptococcus pseudopneumoniae. Ferrándiz MJ, Martín-Galiano AJ, Arnanz C, Camacho-Soguero I, Tirado-Vélez JM, de la Campa AG. 8Streptococcus pseudopneumoniae.
  9. Streptococcus pseudopneumoniae.Streptococcus pseudopneumoniae. Streptococcus pneumoniae Streptococcus pseudopneumoniae. Assay validationStreptococcus pseudopneumoniae.
  10. Streptococcus pseudopneumoniae. Streptococcus pseudopneumoniae. Streptococcus pneumoniaeStreptococcus pseudopneumoniae. Streptococcus pseudopneumoniae.Streptococcus pseudopneumoniae.
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