Sensitization of Staphylococcus aureus to methicillin and other antibiotics in vitro and in vivo in the presence of HAMLET.
Sensitization of Staphylococcus aureus to methicillin and other antibiotics in vitro and in vivo in the presence of HAMLET.
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DOI：
10.1371/journal.pone.0063158
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hakansson AP
中科院分区：
文献类型：
--
作者：
Marks LR;Clementi EA;Hakansson AP
哈姆雷特（对肿瘤细胞具有致死性的人α-乳白蛋白）是一种来自人乳的蛋白质-脂质复合物，具有杀肿瘤和杀菌活性。哈姆雷特对一些呼吸道病原体具有相当特异的杀菌活性，对肺炎链球菌的活性最高，但对大多数其他细菌病原体（包括葡萄球菌）缺乏活性。尽管如此，在S.在不敏感的生物体中也检测到较低程度的肺炎链球菌。在这项研究中，我们证明了哈姆雷特作为一种抗微生物佐剂，可以增加广谱抗生素（甲氧西林，万古霉素，庆大霉素和红霉素）对多药耐药金黄色葡萄球菌的活性，在一定程度上，他们变得对这些相同的抗生素敏感，无论是在抗细菌和生物膜细菌的抗微生物测定和鼻咽定植的体内模型。我们表明，哈姆雷特发挥这些作用，具体通过消散质子梯度和诱导钠依赖性钙离子流入，部分去极化质膜，在肺炎球菌死亡诱导相同的机制。这些作用导致青霉素、庆大霉素和万古霉素的细胞相关结合和/或摄取增加，尤其是在耐药菌株中。最后，哈姆雷特抑制在抗生素压力下观察到的甲氧西林耐药性增加，并且细菌不会对佐剂产生耐药性，这是该分子的主要有利特征。这些结果强调了哈姆雷特作为一种新型抗菌佐剂的潜力，以增加抗生素对耐药菌株的临床有用性。金黄色。
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex from human milk with both tumoricidal and bactericidal activities. HAMLET exerts a rather specific bactericidal activity against some respiratory pathogens, with highest activity against Streptococcus pneumoniae, but lacks activity against most other bacterial pathogens, including Staphylococci. Still, ion transport associated with death in S. pneumoniae is also detected to a lower degree in insensitive organisms. In this study we demonstrate that HAMLET acts as an antimicrobial adjuvant that can increase the activity of a broad spectrum of antibiotics (methicillin, vancomycin, gentamicin and erythromycin) against multi-drug resistant Staphylococcus aureus, to a degree where they become sensitive to those same antibiotics, both in antimicrobial assays against planktonic and biofilm bacteria and in an in vivo model of nasopharyngeal colonization. We show that HAMLET exerts these effects specifically by dissipating the proton gradient and inducing a sodium-dependent calcium influx that partially depolarizes the plasma membrane, the same mechanism induced during pneumococcal death. These effects results in an increased cell associated binding and/or uptake of penicillin, gentamicin and vancomycin, especially in resistant stains. Finally, HAMLET inhibits the increased resistance of methicillin seen under antibiotic pressure and the bacteria do not become resistant to the adjuvant, which is a major advantageous feature of the molecule. These results highlight HAMLET as a novel antimicrobial adjuvant with the potential to increase the clinical usefulness of antibiotics against drug resistant strains of S. aureus.
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DOI：
10.1126/science.1176667
发表时间：
2009-08-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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Pages, Jean-Marie
影响因子：
3.5
作者：
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影响因子：
2.8
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