School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
UMR_MD1, U-1261, Aix Marseille Universite, INSERM, SSA, MCT, 13385 Marseille, France.
Bioorg Med Chem. 2021 May 15;38:116110. doi: 10.1016/j.bmc.2021.116110. Epub 2021 Mar 14.
In our search for new antibiotic adjuvants as a novel strategy to deal with the emergence of multi-drug resistant (MDR) bacteria, a series of succinylprimaquine-polyamine (SPQ-PA) conjugates and derivatives of a cationic amphiphilic nature have been prepared. Evaluation of these primaquine conjugates for intrinsic antimicrobial properties and the ability to restore the antibiotic activity of doxycycline identified two derivatives, SPQ-PA3-8-3 and SPQ-PA3-10-3 that exhibited intrinsic activity against the Gram-positive bacteria Staphylococcus aureus and the yeast Cryptococcus neoformans. None of the analogues were active against the Gram-negative bacterium Pseudomonas aeruginosa. However, in the presence of a sub-therapeutic amount of doxycycline (4.5 µM), both SPQ-PA3-4-3 and SPQ-PA3-10-3 compounds displayed potent antibiotic adjuvant properties against P. aeruginosa, with MIC's of 6.25 µM. A series of derivatives were prepared to investigate the structure-activity relationship that explored the influence of both a simplified aryl lipophilic substituent and variation of the length of the polyamine scaffold on observed intrinsic antimicrobial properties and the ability to potentiate the action of doxycycline against P. aeruginosa.
在寻找新的抗生素佐剂以应对多药耐药（MDR）细菌出现的新策略中，我们制备了一系列琥珀酰基伯氨喹-多胺（SPQ-PA）缀合物和具有阳离子两亲性的衍生物。评估这些伯氨喹缀合物的固有抗菌特性和恢复多西环素抗菌活性的能力，确定了两种衍生物 SPQ-PA3-8-3 和 SPQ-PA3-10-3，它们对革兰氏阳性菌金黄色葡萄球菌和酵母新生隐球菌具有固有活性。没有一种类似物对革兰氏阴性菌铜绿假单胞菌有活性。然而，在亚治疗剂量的多西环素（4.5µM）存在下，两种 SPQ-PA3-4-3 和 SPQ-PA3-10-3 化合物均对铜绿假单胞菌显示出有效的抗生素佐剂特性，MIC 值为 6.25µM。我们制备了一系列衍生物，以研究构效关系，探索简化芳基亲脂取代基和多胺支架长度变化对固有抗菌特性和增强多西环素对铜绿假单胞菌作用的影响。
