Biometals ( IF 4.1 ) Pub Date : 2020-11-06 , DOI: 10.1007/s10534-020-00263-z Dimitris Matiadis 1 , Maria Karagiaouri 2 , Barbara Mavroidi 1 , Katarzyna E Nowak 3 , Georgios Katsipis 2 , Maria Pelecanou 1 , Anastasia Pantazaki 2 , Marina Sagnou 1
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Abstract
The emergence of resistant bacterial strains mainly due to misuse of antibiotics has seriously affected our ability to treat bacterial illness, and the development of new classes of potent antimicrobial agents is desperately needed. In this study, we report the efficient synthesis of a new pyrazoline-pyridine containing ligand L1 which acts as an NN-donor for the formation of a novel silver (I) complex 2. The free ligand did not show antibacterial activity. High potency was exhibited by the complex against three Gram-negative bacteria, namely Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumanii with the minimum inhibitory concentration (MIC) ranging between 4 and 16 μg/mL (4.2–16.7 μM), and excellent activity against the fungi Candida albicans and Cryptococcus neoformans (MIC ≤ 0.25 μg/mL = 0.26 μM). Moreover, no hemolytic activity within the tested concentration range was observed. In addition to the planktonic growth inhibition, the biofilm formation of both Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa was significantly reduced by the complex at MIC concentrations in a dose-dependent manner for Pseudomonas aeruginosa, whereas a biphasic response was obtained for MRSA showing that the sub-MIC doses enhanced biofilm formation before its reduction at higher concentration. Finally, complex 2 exhibited strong DNA binding with a large drop in DNA viscosity indicating the absence of classical intercalation and suggesting the participation of the silver ion in DNA binding which may be related to its antibacterial activity. Taken together, the current results reveal that the pyrazoline-pyridine silver complexes are of high interest as novel antibacterial agents, justifying further in vitro and in vivo investigation.
Graphic abstract
中文翻译：
吡唑啉-吡啶银 (I) 复合物的合成和抗菌评价：DNA 相互作用和抗生物膜活性
摘要
主要由于滥用抗生素而产生的耐药菌株的出现严重影响了我们治疗细菌性疾病的能力，迫切需要开发新型强效抗菌药物。在这项研究中，我们报告了一种新的含有吡唑啉-吡啶的配体L1的有效合成，该配体作为 NN 供体用于形成新型银 (I) 配合物2。游离配体不显示抗菌活性。该复合物对三种革兰氏阴性菌，即大肠杆菌、铜绿假单胞菌和鲍曼不动杆菌表现出高效力最小抑菌浓度 (MIC) 范围在 4 到 16 μg/mL (4.2–16.7 μM) 之间，对真菌白色念珠菌和新型隐球菌具有出色的活性（MIC ≤ 0.25 μg/mL = 0.26 μM）。此外，在测试浓度范围内未观察到溶血活性。除了浮游生长抑制，既耐甲氧西林的生物膜形成的金黄色葡萄球菌（MRSA）和绿脓杆菌是显著通过复合在MIC的浓度降低了剂量依赖的方式绿脓杆菌，而 MRSA 获得了双相反应，表明亚 MIC 剂量增强了生物膜形成，然后在较高浓度下减少。最后，复合物2表现出强 DNA 结合，DNA 粘度大幅下降，表明没有经典嵌入，并表明银离子参与 DNA 结合，这可能与其抗菌活性有关。综上所述，目前的结果表明，吡唑啉-吡啶银复合物作为新型抗菌剂具有很高的价值，证明进一步进行体外和体内研究是合理的。
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