research groups

Bacterial Pathogenesis

summary

Our laboratory has made multiple findings and developed study tools on the molecular mechanisms of signal transduction in the enterobacteria Salmonella enterica and Serratia marcescens, primary and opportunistic clinically relevant pathogens, respectively. We focus on the characterization of signal transduction systems of the two-component family (TCS), which are central regulators that detect signals from the extra- and intra-host environment and modulate the temporal-spatial expression of key phenotypes in the progression of infections. bacterial. Due to the global incidence of bacterial infections, and the acquisition of resistance and progressive loss of effectiveness of antibacterial drugs, we address the challenge of developing strategies for screening, identification and/or synthesis of new chemical agents that block virulence by targeting TCS and pathogenic effectors.
GROUP DIRECTOR
García Véscovi, Eleonora

Sede:

CCT

Email:

garciavescovi@ibr-conicet.gov.ar
Project Directors
Associated researchers
  • Mariscotti, Javier Fernando
PhD POST-Fellows
  • Tuttobene, Marisel Romina
PhD Fellows
  • Arango G.I., Brayan Stiven
  • Sartori, Maria Sol
Undergraduate Students
  • Calgaterra, Gimena Belen
technicians

RESEARCH LINES

Screening and identification of new antibacterial compounds

The emergence of multi-resistant pathogenic bacteria threatensthe success in the treatment of most infectious illnesses, turning ineffective the antibiotic drugs currently administered. This makes urgent the development of new antibacterial agents directed against alternative bacterial targets.  Our laboratory group is dedicated to identify novel compounds that interfere with bacterial pathogenic processes with the final aim of developing anti-virulence drugs that can be used as antimicrobials for therapeutic use.

From the early beginning, our team was dedicated to the analysis of the two-component family of regulatory systems, and focused on the Salmonella typhimuriumPhoP/PhoQ-dependent signal transduction regulatory cascade. This signal transduction system controls the expression of more than 60 genes involved in magnesium homeostasis, resistance to antimicrobial peptides, non-phagocytic cells invasion and survival along the infective cycle within the host. By using biochemical, genetic and molecular biology approaches, we have defined essential aspects of the PhoP/PhoQ-dependent transduction mechanism: signals detection, PhoP/PhoQ specific recognition, phosphotransfer reactions and dynamic cytolocalization of the components of the system. In parallel, we have determined the identity and expression mechanisms of PhoP/PhoQ-dependent genes. With this knowledge, and taking into account that two-component systems are ubiquitous in bacteria but absent in mammalian cells, our group focuses in the identification of new compounds that are able to modulate the PhoP/PhoQ system , with potential pharmacological use.

Gene regulation and bacterial pathogenesis in Serratia marcescens

S. marcescens is an etiological agent of urinary tract and respiratory infections, endocarditis, osteomyelitis, eye and wound infections, meningitis and sepsis. Serratia shows a high incidence in immunocompromised patients and also in neonatal intensive care units. The analysis of pathogenic mechanisms of opportunistic bacteria such as Serratia, with high impact in under-developed and developing countries, has given priority to the understanding of antibiotic multiple resistances. This information is valuable to adopt strategies to fight infectionsin the short term. However, for most opportunistic bacteria, the analysis of virulence mechanisms and factors involved in the long term pathogen-host interaction (colonization, invasion and dissemination) has been relegated. This knowledge constitutes the basis for the development of alternative therapeutic targets.

Our laboratory has demonstrated that Serratia marcescens has the capacity not only to promote its internalization in non-phagocytic cells but also to survive and proliferate intracellularly. We showed that the Serratia-containing vacuole deploys a traffic pathway that diverges from the canonical route, avoiding the physiological mechanisms that promote bacterial elimination. After intracellular proliferation, the expression of a bacterial effector allows Serratia to egress from the invaded cell by a non-lytic process, granting its dissemination. In parallel, we have demonstrated that phenotypes such as swimming and swarming motility, adherence to host cells, the expression levels of the cytolysinsShlA and PhlA, and the ability to produce outer membrane vesicles depend on the activation status of the Rcs signal transduction system. These results revealed that the Rcs system is key for the proper temporal and spatial regulation of the Serratia pathogenic traits expression.

In sum, our group has elucidated a repertoire of adaptive regulatory mechanisms and specific effectors deployed by Serratia to survive, proliferate and disseminate outside and inside the host. Because all of these features, Serratia marcescens constitutes an optimal model to further contribute to the understanding of bacteria-host interaction.

“Unraveling the Role of UilS, a urea-induced acyl-homoserine lactonase that enhances Serratia marcescens fitness, interbacterial competition and urinary tract infection” 

Autores: Marisel R. Tuttobene, Brayan S. Arango Gil, Gisela Di Venanzio, Javier F. Mariscotti, Rodrigo Sieira, Mario F. Feldman, María Soledad Ramirez and Eleonora García Véscovi 

Journal: mBio

Downloads:

mBio-Tuttobene et al-Supplementary Material

mBio Tuttobene et al- Table S1

 

Images of our research lines

PUBLICATIONS AND PATENTS

A natural product from Streptomyces targets PhoP and exerts antivirulence action against Salmonella enterica.

J. Antimicrobial Chemotherapy. In press. DOI: 10.1093/jac/dkac278. Bruna RE, Casal A, Bercovich B, Gramajo H, Rodríguez E and García Véscovi E* (2022).

A natural product from Streptomyces targets PhoP and exerts antivirulence action against Salmonella enterica.

J. Antimicrobial Chemotherapy. In press. DOI: 10.1093/jac/dkac278. Bruna RE, Casal A, Bercovich B, Gramajo H, Rodríguez E and García Véscovi E* (2022).
DOI

Effect-Directed Synthesis of PhoP/PhoQ Inhibitors to Regulate Salmonella Virulence,

J. Agric. Food Chem., 70, 22, 6755–6763. Cabezudo I, Lobertti CA., García Véscovi* E and Furlan RLE* (2022).

Effect-Directed Synthesis of PhoP/PhoQ Inhibitors to Regulate Salmonella Virulence,

J. Agric. Food Chem., 70, 22, 6755–6763. Cabezudo I, Lobertti CA., García Véscovi* E and Furlan RLE* (2022).
DOI

The fliR gene contributes to the virulence of S. marcescens in a Drosophila intestinal infection model.

Sci Rep Feb 23;12(1):3068. Sina Rahme B, Lestradet M, Di Venanzio G, Ayyaz A, Yamba MW, Lazzaro M, Liégeois S, Garcia Véscovi E, Ferrandon D (2022).

The fliR gene contributes to the virulence of S. marcescens in a Drosophila intestinal infection model.

Sci Rep Feb 23;12(1):3068. Sina Rahme B, Lestradet M, Di Venanzio G, Ayyaz A, Yamba MW, Lazzaro M, Liégeois S, Garcia Véscovi E, Ferrandon D (2022).
DOI

Histone-like nucleoid-structuring protein (H-NS) regulatory role in antibiotic resistance in Acinetobacter baumannii.

Sci Rep. 11, 18414, Rodgers D, Le C, Pimentel C, Tuttobene MR, Subils T, Escalante J, Nishimura B, Vescovi EG, Sieira R, Bonomo RA, Tolmasky ME, Ramirez MS. (2021).

Histone-like nucleoid-structuring protein (H-NS) regulatory role in antibiotic resistance in Acinetobacter baumannii.

Sci Rep. 11, 18414, Rodgers D, Le C, Pimentel C, Tuttobene MR, Subils T, Escalante J, Nishimura B, Vescovi EG, Sieira R, Bonomo RA, Tolmasky ME, Ramirez MS. (2021).
DOI

Serratia marcescens RamA expression is under PhoP-dependent control and modulates lipid A-related genes transcription and antibiotic resistance phenotypes.

J. Bacteriol. (2021) Jun 8;203(13):e0052320. Mariscotti, JF, García Véscovi, E*. (2021).

Serratia marcescens RamA expression is under PhoP-dependent control and modulates lipid A-related genes transcription and antibiotic resistance phenotypes.

J. Bacteriol. (2021) Jun 8;203(13):e0052320. Mariscotti, JF, García Véscovi, E*. (2021).
DOI

contacto@conicet.gov.ar

Sede CCT Rosario

Ocampo y Esmeralda, Predio CONICET-Rosario
2000 Rosario, Santa Fe, Argentina
Tel. 54-341-4237070 / 4237500 / 4237200

Sede Facultad de Ciencias Bioquímicas y Farmacéuticas

Universidad Nacional de Rosario - Suipacha 531
2000 Rosario, Santa Fe, Argentina
Tel. +54 341 4350596 / 4350661 / 4351235

Paper Release on @MolMicroEditors👉Research on two-component systems in B. subtilis shows that YvfT/YvfU regulates the yvfRS operon and interacts with DesK/DesR. This reveals cross-regulation between homologous TCSs to fine-tune gene expression in response to environmental cues.