Department of Chemistry, University of Manitoba, Winnipeg, Canada.
Department of Microbiology, University of Manitoba, Winnipeg, Canada.
J Antibiot (Tokyo). 2019 May;72(5):253-259. doi: 10.1038/s41429-019-0153-4. Epub 2019 Feb 13.
The rise in antibiotic resistance among pathogenic microorganisms has created an imbalance in the drugs available for treatment, in part due to the slow development of new antibiotics. Cystic fibrosis (CF) patients are highly susceptible to antibiotic-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Phloroglucinols and related polyketide natural products have demonstrated antimicrobial activity against a number of Gram-positive bacteria including S. aureus. In this study, we investigated a series of acylated phloroglucinol derivatives to determine their potential as lead compounds for the design of novel therapeutics. To assess the activity of these compounds, we determined the minimum inhibitory and bactericidal concentration (MIC and MBC, respectively), the minimum biofilm inhibitory and biofilm eradication concentration (MBIC and MBEC, respectively), and evaluated hemolytic activity, as well as their interaction with clinically relevant antibiotics. Of the 12 compounds tested against MRSA and methicillin-susceptible strains, four showed MIC values ranging from 0.125 to 8 µg ml and all of them were bactericidal. However, none of the compounds were able to eradicate biofilms at the concentrations tested. Three of the four did not display hemolytic activity under the conditions tested. Further studies on the interactions of these compounds with clinically relevant antibiotics showed that phlorodipropanophenone displayed synergistic activity when paired with doxycycline. Our results suggest that these acylated phloroglucinols have potential for being further investigated as antibacterial leads.
抗生素耐药性在病原微生物中的上升导致治疗药物的不平衡，部分原因是新抗生素的开发缓慢。囊性纤维化（CF）患者极易受到抗生素耐药病原体的感染，包括耐甲氧西林金黄色葡萄球菌（MRSA）。根皮苷醇和相关的聚酮天然产物对许多革兰氏阳性菌（包括金黄色葡萄球菌）表现出抗菌活性。在这项研究中，我们研究了一系列酰化根皮苷醇衍生物，以确定它们作为设计新型治疗药物的潜在先导化合物的潜力。为了评估这些化合物的活性，我们确定了最低抑菌和杀菌浓度（MIC 和 MBC）、最低生物膜抑制和生物膜消除浓度（MBIC 和 MBEC），评估了溶血活性以及它们与临床相关抗生素的相互作用。在所测试的 12 种针对 MRSA 和耐甲氧西林金黄色葡萄球菌的化合物中，有 4 种化合物对 MRSA 和耐甲氧西林金黄色葡萄球菌的 MIC 值在 0.125 到 8μg/ml 之间，所有化合物均具有杀菌作用。然而，在测试浓度下，没有一种化合物能够消除生物膜。在测试条件下，这 4 种化合物中的 3 种没有显示出溶血活性。进一步研究这些化合物与临床相关抗生素的相互作用表明，根皮二苯丙酚酮与强力霉素联合使用时表现出协同作用。我们的研究结果表明，这些酰化根皮苷醇具有作为抗菌先导化合物进一步研究的潜力。
