Bacterial infections are becoming prevalent in our society due to the increasing ability of microbes to evade conventional antibiotics. Successful pathogens infections that often diverge in a broad range of diseases, which enable them to escape from target-specific antibiotic therapies. Among those, the life-threatening pathogen Staphylococcus aureus is one of the most successful pathogens, causing different types of severe infections, from acute bacteremia to endocarditis, pneumonia and chronic biofilm-associated infections. How does S. aureus cause these disparate types of infections is currently unknown. However, it is believed that specific yet to be described, extracellular signals are likely to play a role in the adaptation of S. aureus to thrive in different colonization niches and therefore, generate distinct and locally define types of infections. Our laboratory explores signal transduction and cell-cell communication in S. aureus at two different levels to understand the development of staphylococcal infections and improve the strategies to overcome antimicrobial resistance in this pathogen:

Single-cell level

Study of the presence of Functional Membrane Microdomains in bacteria and development of targeting small molecules to prevent infectious diseases.

One of the most sophisticated concepts in membrane organization is the proposed existence of lipid rafts. Membranes of eukaryotic cells organize signal transduction proteins into microdomains or rafts, that are enriched in particular lipids like cholesterol. Lipid rafts are important for the correct functionality of numerous cellular functions, and their disruption causes serious defects in several signal transduction processes. The assembly of lipid rafts in eukaryotes has been considered a fundamental step during the evolution of cellular complexity, suggesting that prokaryotes were too simple organisms to require such a sophisticated organization of their membranes. However, my group discovered that bacteria organize many membrane-related cellular processes in Functional Membrane Microdomains (FMMs) constituted by specific lipids, similar to the lipid rafts that are found in eukaryotic cells. Importantly, the perturbation of FMMs inevitably leads to a potent and simultaneous impairment of all harbored signal transduction pathways, which causes a potent inhibition of the infective potential in pathogenic bacteria. The discovery of FMMs represents a new concept in biology that we address in this laboratory using the nosocomial pathogen Staphylococcus aureus as working model. We aim to understand the structural components involved in the assembly and maintenance of FMMs; the biological role of FMMs in regulating infection-related process and the feasibility of targeting the integrity of FMMs as a new strategy for anti-microbial therapy. To achieve these goals, we currently work to demonstrate that FMMs are integrated membrane platforms specialized in membrane organization and naturally present in all bacterial membranes. Furthermore, we work to understand the biological role of FMMs with special emphasis on their influence in regulating infection-related process. In addition to this, our most important task is to demonstrate the possibilities to disassemble FMMs as a new strategy for anti-microbial therapy, using our collection of new anti-FMMs molecules.

Community level

Cell-cell communication within staphylococcal biofilms.

Antibiotics are the primary treatment for bacterial infections but the number of effective antibiotics is decreasing with the rising numbers of multi-drug resistant pathogens. However, the development of antibiotic resistance is also a naturally occurring process in bacteria, which is not exclusively restricted to clinically relevant species, which raises the possibility that the rising levels of antibiotic resistance in problem pathogens may also be influenced by competitive microbial interactions, similar to what occurs in natural environments. Bacterial colonization involves the formation of surface-associated aggregates or biofilms. Biofilm-encased cells are subjected to strong natural selection, as they compete for space and nutrients, which can shape microbial phenotypes and diversity. These conditions give rise to a heterogeneous population of genetically different bacteria that display characteristics that are relevant to understanding the progression of an infection. We investigate the possible factors involved in shaping the diversity of MRSA biofilms in which the pathogen could evolve new phenotypes that resist antibiotic treatment to ultimately elucidate how bacterial interactions play a role in microbial evolution and can serve to explain the diversification of key clinical phenotypes. We have developed a new biofilm formation assay in S. aureus that allow us studying the evolution of this pathogen in real time. This approach opens brand-new possibilities to explore the interactions that occur in heterogeneous population of mixed communities of bacteria, which can be relevant to understand the progression of an infection. We are currently adapting the environmental niches, which can shape microbial phenotypes and diversity to mimic the environmental conditions that can be found in specific organs that are more susceptible for staphylococcal infections. We aim to directly monitor the evolution of antibiotic resistance with animal models in which I can reproduce more reliably the progression of an infection.