Blanca María Fernández Ciruelos

Name: Blanca María Fernández Ciruelos

University of Wageningen
Host-Microbes Interactomic Group
De Elst 1

Throughout my years of study, I have been progressively specializing in microbiology and infectious diseases. Firstly, I studied BSc in Biotechnology in Universidad de Salamanca, Spain, which provided me a general overview of molecular biology and microbiology, in addition to multiple other relevant disciplines such as genetics and bioinformatics. During my Bachelor Thesis I studied the “regulation of genomic stability in response to DNA damage” in Saccharomyces cerevisiae under the supervision of Dr. Monica Segurado (IBFG) where I learnt about genetics and mutant construction.

My increasing interest in microbiology over the years in college led me to decide to immerse a bit more into this field by studying MSc in Molecular Medicine, with a Microbes & Infection specialization at the University of Sheffield, UK. This wonderful abroad experience not was only a perfect chance to improve my English skills and work in an international team, but also led me to discover the fascinating field of antibiotic resistance. Indeed, thanks to my master research project “Molecular basis of C. difficile resistance to beta-lactam antibiotics” under the supervision of Dr. Stephane Mesnage, I got familiarised with a lot of microbiology techniques such as molecular biology research, mutant construction, cloning and sequence analysis, susceptibility phenotypic assays, biochemical assays and general bacteriology methods. Also, both my final degree and research project allowed me to work individually on the lab, improving my multi-tasking and troubleshooting skills.

ESR4 – Development of new antibiotics targeting histidine kinases regulating virulence mechanisms.

My project

Bacterial two component systems (TCSs) are signalling systems involved in bacterial adaption to environment, bacterial virulence regulation and some antibiotic resistance pathways. TCSs are promising new targets for novel antimicrobials and anti-infectives development. Commonly, TCSs consist on a sensor histidine kinase (HK) and a cognate response regulator (RR) that modulates gene expression in response to the stimulus. Previous research in the group identified compounds that inhibit the autophosphorylation of TCS HK, key step in TCS signalling pathway. Novel inhibitors of the autophosphorylation of TCS HK are also being generated by collaborators. In this project, we aim to: i) provide biological information to the collaborators to support and guide structure based development and synthesis of more potent antibacterials or anti-infectives based on HK autophosphorylation.

Biological information will include inhibitory concentrations, in vitro toxicity, potential of resistance development, and off-target activity ii) to establish an in vivo reporter gene assay for QseC-regulated genes in a relevant pathogen Enteropathogenic E. coli. QseC is a relevant TCS involved in the regulation of virulence. This reporter gene assay will be used to screen for new inhibitors and gain a better understanding of the regulation of virulence in this organism, iii) test the absorption of the most promising compounds via the oral route using intestinal organoids and iv) assess the efficacy and toxicity of lead compounds in a mammalian infection model with E. faecium, a relevant Gram-positive pathogen important cause of nosocomial infections.