Żelaszczyk Dorota, Chmiel Aneta, Gunia-Krzyżak Agnieszka, Marona Henryk, Krzyżek Paweł, Dworak Kinga, Skiba-Kurek Iwona, Karczewska Elżbieta, Popiół Justyna, Pękala Elżbieta, Żmudzki Paweł, Ziąbka Magdalena, Klesiewicz Karolina
Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow 30-688, Poland.
Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow 30-688, Poland.
Bioorg Chem. 2024 Dec;153:107755. doi: 10.1016/j.bioorg.2024.107755. Epub 2024 Aug 30.
Helicobacter pylori (H. pylori) cause chronic inflammation of the gastric mucosa which can lead to epithelial atrophy and metaplasia resulting in peptic ulcer disease and gastric cancer. The increasing resistance of H. pylori to antibiotics and chemotherapeutics used to treat the infection is a serious problem. However, it has been confirmed that the introduction of effective anti-H. pylori therapy can prevent the progression to cancerous changes. This problem calls for the search for new and effective therapies. Xanthones are a group of compounds with extensive biological activities, including antibacterial activity, also against H. pylori. Addressing this issue, the aim of the study was to evaluate the potential of a group of 13 xanthone derivatives against susceptible and resistant H. pylori strains. Moreover, our objective was to conduct tests aimed at determining their ability to inhibit biofilm formation. The antimicrobial evaluation revealed that benzylpiperazine coupled at the C-2 position to xanthone (compounds C11 and C12) had good selective bacteriostatic activity against reference and clinical H. pylori strains (MBC/MIC ratio >4) but with no activity against other bacteria such as Staphylococcus aureus, Escherichia coli, and Lactobacillus paracasei. Analysis of the activity of compounds C11 and C12 against the biofilm formed by H. pylori strain ATCC 700684, and the clinical strain showed that these compounds caused a significant reduction in the amount of biofilm produced (5-20×). Moreover, cell viability analysis confirmed a 3-4× reduction in the viability of cells forming biofilm after treatment with C11 and C12. Finally,both compounds did not impair human fibroblast viability at tested concentrations and were not mutagenic in the Ames test. Therefore, they could be promising leads as antibacterial candidates for multidrug-resistant strains of H. pylori.
幽门螺杆菌（H. pylori）会引发胃黏膜的慢性炎症，进而导致上皮萎缩和化生，引发消化性溃疡疾病和胃癌。幽门螺杆菌对用于治疗该感染的抗生素和化疗药物的耐药性不断增加，这是一个严重的问题。然而，已证实采用有效的抗幽门螺杆菌疗法可预防病情发展为癌变。这个问题促使人们寻找新的有效疗法。呫吨酮是一类具有广泛生物活性的化合物，包括抗菌活性，对幽门螺杆菌也有抗菌作用。针对这一问题，本研究的目的是评估一组13种呫吨酮衍生物对敏感和耐药幽门螺杆菌菌株的潜力。此外，我们的目标是进行测试，以确定它们抑制生物膜形成的能力。抗菌评估显示，在呫吨酮的C-2位连接苄基哌嗪（化合物C11和C12）对参考和临床幽门螺杆菌菌株具有良好的选择性抑菌活性（MBC/MIC比值>4），但对其他细菌如金黄色葡萄球菌、大肠杆菌和副干酪乳杆菌没有活性。对化合物C11和C12针对幽门螺杆菌ATCC 700684菌株和临床菌株形成的生物膜的活性分析表明，这些化合物使生物膜产生量显著减少（5 - 20倍）。此外，细胞活力分析证实，用C11和C12处理后，形成生物膜的细胞活力降低了3 - 4倍。最后，在测试浓度下，这两种化合物均未损害人成纤维细胞的活力，且在艾姆斯试验中无致突变性。因此，它们有望成为耐多药幽门螺杆菌菌株抗菌候选药物的先导化合物。
