In Vitro and In Silico Evaluation of the Potentiating Effect of Thiadiazine Derivatives Against Multidrug-Resistant (MDR) Bacterial Strains
Evandro Gomes da Silva Júnior, Ingrid Gonçalves Pereira Dantas, Matheus dos Santos Lourenço, João Arthur de Oliveira Borges, Isaac Moura Araújo, José Thyálisson da Costa Silva, Ana Carolina Ferreira Araújo, Priscilla Ramos Freitas Alexandre, Janaína Esmeraldo Rocha, Maria Karollyna do Nascimento Silva Leandro, Igor José dos Santos Nascimento, João Xavier de Araújo-Júnior, Edeildo Ferreira da Silva-Júnior, Thiago Mendonça de Aquino, Francisco Jaime Bezerra Mendonça Junior, Emmanuel Silva Marinho, Hélcio Silva dos Santos, António Raposo, Henrique Douglas Melo CoutinhoBackground/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections.