POTENCIAL BIOATIVO DE ESPÉCIES DO CERRADO FRENTE A DIFERENTES MICRORGANISMOS E REVISÃO SISTEMÁTICA SOBRE OS MECANISMOS DE AÇÃO DE TERPENOS SOBRE STAPHYLOCOCCUS AUREUS

Abstract

Antimicrobial resistance represents one of the greatest challenges to contemporary public health, with methicillin-resistant Staphylococcus aureus (MRSA) standing out as a pathogen associated with high morbidity and mortality. In this context, natural products emerge as promising sources of bioactive molecules. This thesis was developed in three complementary axes. In the first, a preliminary screening was conducted with ethanolic extracts of five Cerrado species (Equisetum piramidale, Porophyllum ruderale, Smilax fluminensis, Pouteria ramiflora, and Tapirira obtusa). These extracts were tested against clinically relevant microorganisms (Candida albicans, C. parapsilosis, C. krusei, C. glabrata, MRSA, and Klebsiella pneumoniae) and subjected to antioxidant and antiproliferative assays in human tumor cell lines. Phytochemical analysis revealed phenolic compounds, flavonoids, steroids, tannins, and saponins in all extracts. Antioxidant activity exceeded 50%, with T. obtusa showing the highest value. Regarding antimicrobial activity, S. fluminensis exhibited fungicidal effect against C. glabrata (MIC = 500 μg/mL), while T. obtusa demonstrated antibacterial activity against MRSA (MIC = 1000 μg/mL). T. obtusa also displayed antiproliferative activity against the renal 786-0 cell line, high selectivity (SI = 24.61), and absence of toxicity in non-tumor cells. In the second axis, a more detailed investigation of T. obtusa ethanolic extract, collected in the Cerrado (MS, Brazil), was performed. The extract was chemically characterized and subjected to antioxidant, antimicrobial, antibiofilm, cytotoxicity, and mutagenicity assays. Chemical analysis inferred the presence of alkamides, alkanolamides, alkylphenols, and anacardic acids. The extract exhibited antioxidant activity (IC₅₀ = 29.56 μg/mL) and antimicrobial effect against 20 clinical isolates of S. aureus (10 MSSA, 10 MRSA), with MIC values ranging from >1.95 to 1000 μg/mL. Strong activity (MIC < 100 μg/mL) was observed in 70% of isolates, significantly more pronounced against MRSA (p = 0.01). No inhibition of biofilm formation was detected. Cytotoxicity assays revealed a dose-dependent effect in non-tumor cell lines (GI₅₀ = 18.55–20.92 μg/mL; LC₅₀ = 77.6–97.7 μg/mL), but with high selectivity against MRSA (SI ≥ 10 in some isolates). The Ames test showed no mutagenic activity in Salmonella Typhimurium, regardless of metabolic activation. In the third axis, a systematic review was conducted on the mechanisms of action of terpenes against S. aureus, based on searches in international databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library, Scielo, BVS/LILACS, and SciFinder) up to May 30, 2025, following PRISMA guidelines. Nineteen original studies were included, revealing multiple mechanisms of action, such as structural alterations of the cytoplasmic membrane, interference in DNA, RNA, and protein synthesis, disruption of energy metabolism, induction of oxidative stress, and modulation of quorum sensing. Synergistic effects with conventional antibiotics were also observed. Despite advances, methodological heterogeneity and the predominance of in vitro studies highlight the need for experimental standardization, functional validation of specific targets (such as PBP2a), and in vivo investigations incorporating pharmacodynamics and toxicity, before any clinical translation. Taken together, the results of this thesis indicate the potential of T. obtusa as a natural source for new antimicrobial agents and reinforce the role of terpenes as strategic candidates in tackling antimicrobial resistance.