Muniz Débora Feitosa, Pereira Raimundo Luiz Silva, Freitas Priscilla Ramos, de Araújo Ana Carolina Justino, Santos Barbosa Cristina Rodrigues Dos, de Menezes Irwin Rose Alencar, de Melo Coutinho Henrique Douglas, Tintino Saulo Relison, Costa Victor Hugo Nunes Soares, da Silva Lucas Oliveira, Brondani Dalci José, Oliveira-Tintino Cícera Datiane de Morais, da Silva Teresinha Gonçalves
Pharmacotoxicological Prospecting Laboratory of Natural Products (BIOFARMATOX), Department of Antibiotics, Federal University of Pernambuco, Brazil.
Laboratory of Microbiology and Molecular Biology (LMBM), Department of Biological Chemistry/CCBS/URCA, Brazil.
Arch Biochem Biophys. 2025 Sep;771:110512. doi: 10.1016/j.abb.2025.110512. Epub 2025 Jun 16.
The production of the β-lactamase enzyme and the presence of efflux pumps in Staphylococcus aureus represent crucial mechanisms in antibiotic resistance. This microorganism constitutes a serious public health problem, triggering hospital-acquired infections and, in extreme cases, resulting in the death of the host. Thus, the development of an effective medication against multidrug-resistant bacteria becomes imperative, minimizing side effects. In this study, six semicarbazone and thiosemicarbazone derivatives (3a, 3b, 3c, 3d, 3e and 3f) were evaluated against the strains K4414, K4100, and K2068, which have QacA/B, QacC, and MepA efflux systems, respectively, with K4414 and K4100 producing β-lactamases. Direct antibacterial activity and β-lactamase inhibition were analyzed using the broth microdilution method, determining the minimum inhibitory concentration (MIC). The ability to inhibit efflux pumps was assessed using the MIC of substances at sub-inhibitory concentrations, in combination with the antibiotics ampicillin, oxacillin, ciprofloxacin, and the DNA intercalating dye, ethidium bromide. Although all compounds showed MIC values > 1024 μg/mL, considered inactive, in combination with antibiotics, a significantly enhancing activity of MIC was observed, especially for the compounds 3d and 3e. These results indicate that 3d and 3e have the potential to act as antibiotic enhancers. Subsequent studies can be conducted to elucidate their specific mechanisms of action, paving the way for considering these compounds as valuable alternatives in the pharmaceutical industry.
金黄色葡萄球菌中β-内酰胺酶的产生以及外排泵的存在是抗生素耐药性的关键机制。这种微生物构成了严重的公共卫生问题，引发医院获得性感染，在极端情况下，会导致宿主死亡。因此，开发一种针对多重耐药细菌的有效药物变得势在必行，同时要尽量减少副作用。在本研究中，对六种氨基脲和硫代氨基脲衍生物（3a、3b、3c、3d、3e和3f）进行了评估，它们分别针对具有QacA/B、QacC和MepA外排系统的K4414、K4100和K2068菌株，其中K4414和K4100会产生β-内酰胺酶。使用肉汤微量稀释法分析直接抗菌活性和β-内酰胺酶抑制作用，确定最低抑菌浓度（MIC）。使用亚抑菌浓度的物质的MIC，并结合抗生素氨苄西林、苯唑西林、环丙沙星和DNA嵌入染料溴化乙锭，评估抑制外排泵的能力。尽管所有化合物的MIC值均>1024μg/mL，被认为无活性，但与抗生素联合使用时，观察到MIC有显著增强的活性，尤其是化合物3d和3e。这些结果表明，3d和3e有潜力作为抗生素增强剂。后续研究可以阐明它们的具体作用机制，为将这些化合物视为制药行业中有价值的替代品铺平道路。
