CNC.IBILI

Therapy5 | Main Goals

The group’s interests are focused on the biological traits of mycobacteria and fungi that drive their success as facultative intracellular infectious agents and as opportunistic agents of human infection and its resistance to antimicrobials acquired through the misuse of drugs, enabling these microbes to withstand attack by antimicrobials, leading to poorer prognosis and increasing the risk of infections dissemination.
Antifungal misuse in health, in environment or in agriculture, led to resistant or less susceptible human fungal pathogens decreasing the efficiency of therapies and increasing the health-associated costs. In A. infectoria, we intend to characterize one of the enzymes responsible for synthesis of chitin, a class V Chs, because it is crucial for the synergy between 2 groups of antifungals (Fernandes et al, MS submitted). With A Casadevall (Albert Einstein School of Medicine, USA) we pursue the studies to answer the question: release of extracellular vesicles by A. infectoria: a virulence trait or a build-up tool? One of our main objectives over the next 5-year period includes unraveling the role of adenosine receptors in the fungal resistance to phagocytic attack and the impact of ageing, both in vitro and in vivo. The trafficking and arrest of A2AR in phagolysosome membrane following phagocytosis is being studied using an A2A-GFP construct. The full characterization of this process, namely using in vivo models, is an ongoing work together with RA Cunha (CNC) and with JR Meyer-Fernandes (UFRJ, Brasil). We are studying how an A2AR antagonist ameliorates the infection of skin cells (keratynocytes) by C. albicans. With S Ribeiro (IBMC) we will pursue studying how codon ambiguity influences phagocytosis. The nature of MMYRG’s research efforts, the new inclusion of Post-docs, and the ongoing collaborations will to achieve funding from funding agencies and entities such as MSD, The Foundation for AIDS Research (amfAR) and ERC.

While drug-sensitive tuberculosis (TB) can be treated and only about 2% TB-related deaths occur in developed countries, new strains resistant to most classes of antibiotics present far greater challenges. Second-line options impart severe side-effects, poor patient compliance and high mortality rates. Annually, TB-related costs in the EU reach 6 billion euro, highly unacceptable for an alleged “disease of the past”. Last decade’s genomic breakthroughs allowed new insights into the biology of TB but many gene functions and metabolic pathways are still enigmatic, which inevitably protracts the path toward new drugs for drug-resistant TB. Since the methylglucose lipopolysaccharide (MGLP) was identified in 1964 but the genes remain enigmatic, we will identify all genes and proceed to structure-guided drug discovery. So far, we deciphered the structures of essential enzymes in this pathway to establish experimental scaffolds for 1) drug libraries screenings and 2) drug design with fragment-based technology. Advantages over library screenings are the small size of libraries required and the huge capacity to explore the target chemical space to enhance specificity. Enzyme inhibition, viability assays and pharmacological profiling in cell/animal models will make use of the know-how assembled in the “Molecular Therapies” strand. We will implement this technology with far-reaching implications for disorders in focus across all strands. Our long-term goals (2015-2020) include the implementation of a research line to explore microbe-gut-metabolism and microbe-gut-brain links in disease, since abnormal gut microbiota (dysbiosis) are hallmarks of obesity, diabetes, autism, depression and neurodegenerative disorders. We assembled a multidisciplinary team of microbiologists, neuroscientists, bioinformaticians and physicians to probe such links in brain diseases. Funding prospects for 2015-2020 include the Gates Foundation, The Michael J. Fox Foundation and an ERC Synergy Grant.