Medical Treatment & Drug Development

Post-Doctoral Fellowships


Loss of robustness as the key to drug repositioning

250,000 people die every year in the European Union because antibiotics could not cure their infection, due to a strong resistance of bacteria to different drug treatments. This is why Dr. Pedro Coelho will study bacteria that have lost robustness by changing their genetic code. Certain genes could be fragile, and therefore become new targets for existing drugs. His findings could lead to new treatments of infections that represent millions of human or animal cases around the world.
We are witnessing the rise of pan-resistant bacteria for which no effective therapy is available. From methicillin-resistant Staphylococcus aureus (MRSA) infections to recent outbreaks of resistant strains of Escherichia coli, these almost or totally pan-resistance bacteria are now reaching the community setting.

The Recycling of Antibiotics

There is a dire need for new classes of antimicrobials. Drug repositioning is the finding of new uses for known drugs. Our lab has developed a new bioinformatics strategy, which enabled the repositioning of a known drug as a potential new class of antibiotic. The underlying scientific question was: what are the conditions necessary for the development of robust biological systems? Theoretical work suggests that robustness should only emerge in unpredictable environments but it remained untested. One source of biological robustness is genetic redundancy, where a given biochemical function is encoded by two or more genes. Our lab showed that bacterial intracellular parasites, which live in a predictable environment, have substantially more singletons than could be expected under any model of gene loss (singletons are genes without duplicates), and that this corresponds to an effective loss of genetic redundancy.
We have refined the previous work by compiling and analyzing an extensive list of sequenced parasites along with other information such as taxonomic classification, facultative vs. obligate nature, specific intracellular replication niche. This research led to the hypothesis that intracellular parasites will adapt to one of four different intracellular replication niches. To test this, we built a bioinformatics pipeline that revealed a core set of protein families/domains that characterize bacterial parasites that inhabit in phagolysosomes. These proteins represent fragile functions for a wide range of pathogens. Furthermore, we developed a predictor (80% accuracy) that is able to identify parasites capable of replication in phagolysosomes.
Furthermore, using a bioinformatics approach, we were able to identify three known drugs that should act upon these fragile functions. These drugs could have an extensive range: from Staphylococcus aureus to Mycobacterium tuberculosis. We are currently submitting our theoretical results to experimental validation.

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Fondation Calouste Gulbenkian

Instituto Gulbenkian de Ciência (IGC)





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