Staphylococcus aureus resistente à meticilina: desafios, estratégias terapêuticas e avaliação de novos compostos antibacterianos

Abstract

Antimicrobial resistance has become a global health issue, affecting thousands of individuals. Methicillin resistant Staphylococcus aureus (MRSA) is among the most urgent threats, with high prevalence and limited number of drugs available for treatment.Moreover, the development of new antimicrobials faces significant challenges, including economic, regulatory, and scientific barriers. Thus, it is essential to explore available strategies, identify promising alternatives, and investigate new compounds with potential for treating resistant infections. The aim of this work was to investigate the challenges and alternatives in combating resistance through a narrative literature review, systematically review therapeutic alternatives with in vivo studies in development for MRSA, and to evaluate the antibacterial activity and biocompatibility of compounds with guanidine ligand. For the narrative review, a bibliographic search was conducted in the Science Direct, PubMed, and Scopus databases to address studies on strategies for combating antimicrobial resistance and explore promising alternatives. Articles were selected based on relevance criteria. The systematic review was conducted following PRISMA guidelines, and the search was performed in the Science Direct, PubMed, Web of Science, Scopus, and Embase databases. Keywords related to antimicrobial alternatives against MRSA and in vivo studies were defined, focusing on studies published between 2010 and June 2024. For the research article, compounds were synthesized by functionalizing the bioactive fragment 3,5-diaryliden-4-piperidone with the guanidine group. Antibacterial activity was determined by broth microdilution, in vitro antibiofilm effects were characterized, and ex vivo antibiofilm potential was evaluated in a porcine skin model. Gene expression analysis by RT-qPCR and membrane assays were performed to evaluate the mechanism of action. The analysis of the adjuvant potential was conducted using a checkerboard assay with the standard drug, stability under adverse conditions, and resistance induction were evaluated in a multistep study. Biocompatibility was verified by the Ames test, hemolysis assay with human erythrocytes, and cytotoxicity in human renal and epithelial cells. The results of the narrative review highlighted three main promising antimicrobial alternatives: (1) phage therapy, (2) antimicrobial peptides, and (3) organometallic compounds. Each approach presents advantages and challenges, showing potential for developing therapeutics for resistant microorganisms. The results of the systematic review identified 587 articles, of which 114 studies met the criteria and were analyzed. The investigated alternatives were classified and the main classes included antimicrobial peptides and derivatives; and synthetic and chemical antimicrobial compounds. In vivo models included skin infections, systemic infections, biofilms and infected implants, with organisms such as murine, invertebrates, and pigs, covering different biological systems to assess antimicrobial efficacy. In the research article, three 3,4-dihydropyrimidin-2(1H)-imine compounds (5a, 5b, and 5c) were synthesized and showed antibacterial activity against S. aureus and MRSA. The compounds also exhibited in vitro and ex vivo antibiofilm effects, negative regulation of genes associated with biofilm and virulence, suggesting a multifactorial mechanism of action. Membrane assays demonstrated time- and concentration-dependent effects, indicating this mechanism as complementary. Furthermore, 5a and 5c enhanced the action of oxacillin. The compounds were stable under adverse conditions, exhibited low resistance induction, and showed no toxicity or mutagenic effects. It is concluded that antimicrobial resistance requires the development of innovative therapeutics, and the narrative review highlighted phage therapy, peptides, and organometallic compounds as promising strategies. The systematic review reinforced this perspective, emphasizing MRSA and in vivo studies, also including nanotechnology and light-based therapies. The explored approaches show potential, but bioavailability and regulation are associated challenges. Furthermore, guanidine ligand compounds proved promising for the development of new drugs for MRSA, with antibacterial activity and biocompatibility.