Desenvolvimento de antibióticos inovadores e multifuncionais direcionados para o tratamento de infeções bacterianas associadas a biofilmes

The main goal of MultAntiBiofilm project is the development of new and potent antibiofilm agents/nanosystems based on the rational combination of plant natural products and less effective antibiotics (hybrids based on PP/antibiotic scaffolds), as well as delivery strategies, which can be used to safely/effectively counteract P. aeruginosa/S. aureus biofilm infections (lung/wound).This will allow obtain new hybrid compounds/nanosystems with multiple modes of action, which is an essential requisite to combat biofilms. To successfully achieve the proposed overarching objective, the project workflow must be interactive, incorporating a set of General/Technical/Strategic objectives, aligned with the workplan and project outcomes/impacts. General:GO1.Study the long-term efficacy and action mechanisms of promising PP as antibiofilm agents, elucidating their ability to biofilm interaction/disruption, prevent regrowth, and enhance antibiotic activity. GO2.Develop novel multifunctional antibiofilm agents and approaches to replace/recycle the arsenal of less/non-active antibiotics, addressing the urgent need for effective biofilm control and management. Technical:TO1.Screen selected PP for antibiofilm potential and assesses their interaction/diffusion along the biofilm matrix to identify candidates with highest long-term efficacy (Task1). TO2.Develop stable mixtures by rational combination of PP and commercial antibiotics, evaluate their antibiofilm and efflux-pump inhibitory activity and perform combinatorial analysis to identify synergistic combinations (Task2). TO3.Design/synthesize new hybrids based on the best PP-antibiotic mixtures, refining their structure in the context of antibiofilm/multi-target profile and drug-like properties (Task3). TO4.Predict active hybrids antibiofilm mode of action using computational tools, validate modeling data by in vitro bioassays, and optimize hybrid structures for improved (multi)target-binding affinity/efficacy (Task4). TO5.Develop nanoencapsulated systems to enhance the fine-tuned dual-hybrids target specificity/delivery, optimizing doses and reducing adverse effects (Task5). TO6.Assess the cytotoxicity/efficacy profile of leads/systems using cell culture/3D tissue models, providing valuable insights for further validation and potential clinical use (Task6). Strategic:SO1.Enhance understanding on the use of PP and less effective marketed antibiotics as pharmacophores for the “construction” of PP-antibiotic hybrids, proposing a new strategy for the antibiofilm hybrid-agents development. This aligns with societal and pharmaceutical industry trends favoring environmentally friendly compounds and sustainable practices (PP use/antibiotic recycling).SO2.Foster collaboration/interdisciplinary research to address critical gaps in antibiofilm drug development, leveraging bioinspiration as a driving force and meeting the increasing demand for accessible/natural drug alternatives. SO3.Promote innovation/advancement in antibiofilm research by integrating cutting-edge bioassays, predictive models, combinatorial chemistry, green/efficient synthetic strategies, computational modeling, artificial intelligence/machine learning, nanotechnology and 3D infection models. SO4.Improve translatability and bridge gaps between academic research and healthcare by employing biofilm-tailored studies and models that closely mimic clinically relevant biofilm-associated infections pathogenesis/accurately replicate the host environment.