Ajoene, a Sulfur-Rich Molecule from Garlic, Inhibits Genes Controlled by Quorum Sensing
Ajoene, a Sulfur-Rich Molecule from Garlic, Inhibits Genes Controlled by Quorum Sensing
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DOI：
10.1128/aac.05919-11
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Givskov, Michael
中科院分区：
文献类型：
--
作者：
Jakobsen, Tim Holm;van Gennip, Maria;Givskov, Michael
关于新出现的多重耐药细菌，抗菌药物和新的感染治疗策略的开发应有望成为一个高度优先的研究领域。群体感应（QS）是一种由铜绿假单胞菌等致病菌用于同步参与致病性的特定基因表达的通讯系统，是一种可能的药物靶点。先前的体外和体内研究揭示了粗大蒜提取物对铜绿假单胞菌QS的显著抑制。通过对大蒜提取物的生物测定引导分级分离，我们确定大蒜中存在的主要QS抑制剂是阿焦烯，一种具有抗病原体药物潜力的含硫化合物。通过全面的体外和体内研究，阐明了合成阿焦烯对铜绿假单胞菌的作用。阿焦烯处理的铜绿假单胞菌培养物的DNA微阵列研究揭示了少数但中心QS控制的毒力因子（包括鼠李糖脂）的浓度依赖性衰减。此外，阿焦烯治疗体外生物膜表现出明显的协同作用，与妥布霉素对生物膜的杀伤和停止多形核白细胞的溶解性坏死的抗菌作用。此外，在肺部感染的小鼠模型中，与未处理的对照组相比，在阿焦烯处理的小鼠中检测到感染的铜绿假单胞菌的显著清除。这项研究增加了证明QS干扰化合物在治疗细菌感染中的潜力的实例列表。
In relation to emerging multiresistant bacteria, development of antimicrobials and new treatment strategies of infections should be expected to become a high-priority research area. Quorum sensing (QS), a communication system used by pathogenic bacteria like Pseudomonas aeruginosa to synchronize the expression of specific genes involved in pathogenicity, is a possible drug target. Previous in vitro and in vivo studies revealed a significant inhibition of P. aeruginosa QS by crude garlic extract. By bioassay-guided fractionation of garlic extracts, we determined the primary QS inhibitor present in garlic to be ajoene, a sulfur-containing compound with potential as an antipathogenic drug. By comprehensive in vitro and in vivo studies, the effect of synthetic ajoene toward P. aeruginosa was elucidated. DNA microarray studies of ajoene-treated P. aeruginosa cultures revealed a concentration-dependent attenuation of a few but central QS-controlled virulence factors, including rhamnolipid. Furthermore, ajoene treatment of in vitro biofilms demonstrated a clear synergistic, antimicrobial effect with tobramycin on biofilm killing and a cease in lytic necrosis of polymorphonuclear leukocytes. Furthermore, in a mouse model of pulmonary infection, a significant clearing of infecting P. aeruginosa was detected in ajoene-treated mice compared to a nontreated control group. This study adds to the list of examples demonstrating the potential of QS-interfering compounds in the treatment of bacterial infections.