The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.
The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.
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DOI：
10.1371/journal.pone.0043514
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发表时间：
2012
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
抗击抗生素耐药性是我们这个时代公共卫生面临的最重大挑战之一。随着新型抗生素的引入，耐药性的不可避免地发展，迫切需要开发具有新的作用机制的新的抗菌药物，而这些新的作用机制不容易受到现有耐药机制的影响。其中一种化合物是哈姆雷特，这是一种来自母乳的天然复合体，它使用不同于普通抗生素的机制杀死肺炎链球菌(肺炎球菌)，并对耐药性产生免疫。在这项研究中，我们发现亚致死浓度的哈姆雷特增强了常用抗生素(青霉素、大环内酯类和氨基糖苷类)对肺炎球菌的作用。使用最低抑菌浓度试验和短时杀灭试验，我们大大降低了杀死肺炎球菌所需的抗生素浓度，特别是在哈姆雷特存在的情况下属于临床敏感范围的抗生素耐药菌株。使用体外生物被膜模型和体内鼻咽定植，哈姆雷特和抗生素的组合完全根除了抗生素敏感和耐药菌株在小鼠体内的生物被膜和定植，这是每种药物单独无法做到的。哈姆雷特-抗生素的增强部分是由于抗生素对细菌的可及性增加，但更多地依赖于钙输入和激酶激活，这与哈姆雷特在自身杀死肺炎球菌时使用的激活途径相同。最后，致敏作用并不局限于对哈姆雷特敏感的物种。对哈姆雷特耐药的呼吸道鲍曼不动杆菌和卡他莫拉菌均在哈姆雷特存在下对不同种类的抗生素致敏，激活机制与肺炎球菌相同。综合这些结果，表明存在一种保守的哈姆雷特激活途径，可以绕过细菌中的抗生素耐药性。激活这一途径的能力可能会延长当前治疗武器库的寿命。
The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.