Nova abordagem para melhorar a eficácia antifúngica em espécies patogénicas de Candida com base na terapia antisense

The Oligo4Resistance addresses crucial challenges in the realm of antifungal resistance in Candida infections. The escalating resistance to current antifungal medications is a major concern in clinical settings, necessitating the development of alternative therapies that offer improved efficacy and reduced toxicity. One promising approach involves the use of antisense oligonucleotides (ASOs), which inhibit protein translation by targeting specific mRNA molecules, particularly those associated with antifungal resistance. Recent advancements in oligonucleotide synthesis have led to the creation of synthetic/unnatural oligos, known as nucleic acid mimics (NAMs), which enhance the affinity to targets and resistance to degradation by nucleases. The incorporation of NAMs into ASOs is a key aspect of the Oligo4Resistance project, providing a cutting-edge mean of improving efficacy and stability. ASOs can complement the action of antifungal agents by targeting specific genes responsible by antifungal resistance, reducing the risk of resistance development in Candida. By using ASOs as adjuvant therapy, it may be possible to achieve effective outcomes with lower doses of antifungal agents. This can help reduce the risk of side effects and toxicities associated with high-dose antifungal therapy. The limited penetration of ASOs into yeast cells due to the protective envelope presents a significant challenge. To overcome this hurdle, delivery strategies such as lipoplexes (LPXs) will be utilized. LPXs are macromolecular complexes formed through the electrostatic interaction between cationic liposomes and ASOs of opposite charge. This use of lipoplexes to facilitate the entry of ASOs into yeast cells exemplifies the interdisciplinary nature of the project, combining expertise in molecular biology, drug delivery, and nanotechnology. In this sense, the aim of Oligo4Resistance is to mitigate the escalation of antifungal resistance in C. albicans and C. glabrata by providing an adjuvant therapy based on antisense technology to enhance the efficacy of antifungal agents (azoles and echinocandins). To achieve this, four complementary objectives were defined:?? 1. Identification of “new” molecular signatures involved in Candida antifungal resistance 2. Exploitation and application of ASOs to control key Candida genes involved in FLU and CAS resistance 3. Creation of delivery vehicles for Candida ASOs cargo 4. Validation, in vivo, of the ability of ASOs complexes to enhance the efficacy of FLU and CAS. The objectives of Oligo4Resistance are highly ambitious and go beyond the current state of the art in the field of antifungal drug development. The use of ASOs as a novel therapeutic approach to combat antifungal resistance is innovative and has the potential to revolutionize the treatment of candidiasis. Overall, the ambitious objectives of Oligo4Resistance have the potential to address a critical need in the field of antimicrobial drug development identified by health authorities, both in Portugal and abroad, as a priority axis of intervention to avoid (or at least reduce) the pace of what can be a new pandemic. In conclusion, Oligo4Resistance has the potential to revolutionize the treatment of candidiasis by providing novel therapies that are more effective and less toxic. This could ultimately lead to improved patient outcomes and reduced healthcare costs, without displacing existing antifungal treatments approved in numerous countries.