Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus
Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus
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DOI：
10.1046/j.1365-2958.2001.02539.x
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发表时间：
2001-07-01
影响因子：
3.6
通讯作者：
Williams, P
中科院分区：
文献类型：
--
作者：
McDowell, P;Affas, Z;Williams, P
在金黄色葡萄球菌中，agr位点负责通过群体感应控制毒力基因的表达。由于群体感应的阻断为减轻感染提供了一种新的策略，我们试图对葡萄球菌分泌的自诱导肽（AIP）信号分子的结构、活性和转换获得新的见解。合成了一系列类似物（包括l -丙氨酸和d -氨基酸扫描肽）来确定金黄色葡萄球菌I群AIP中的功能关键残基。因此，我们确定(I) I组AIP在培养上清液中通过形成相应的甲硫酰基硫化物而失活；（ii） I组AIP内酰胺类似物保留了激活agr的能力，这表明AgrC受体的共价修饰不是agr激活的必要先决条件。尽管每个d -氨基酸扫描的AIP类似物都保留了活性，但位于c端中心半胱氨酸的内环氨基酸残基（天冬氨酸）被丙氨酸取代，使I组AIP从激活剂转变为有效的抑制剂。临床金黄色葡萄球菌分离株的新型AIP组筛选显示，与I组AIP不同的是，在丙氨酸扫描定义为关键的相同位置上存在单个氨基酸残基（天冬氨酸到酪氨酸）。虽然这种AIP抑制I组金黄色葡萄球菌菌株，但产生菌株具有依赖内源性肽的功能性agr位点，因此构成了第四个金黄色葡萄球菌AIP信息素组（IV组）。在金黄色葡萄球菌中添加外源性合成AIPs抑制了中毒性休克综合征毒素（TSST-1）和肠毒素C3的产生，证实了群体感应阻断作为一种治疗策略的潜力。
In Staphylococcus aureus, the agr locus is responsible for controlling virulence gene expression via quorum sensing. As the blockade of quorum sensing offers a novel strategy for attenuating infection, we sought to gain novel insights into the structure, activity and turnover of the secreted staphylococcal autoinducing peptide (AIP) signal molecules. A series of analogues (including the L-alanine and D-amino acid scanned peptides) was synthesized to determine the functionally critical residues within the S. aureus group I AIP. As a consequence, we established that (I) the group I AIP is inactivated in culture supernatants by the formation of the corresponding methionyl sulphoxide; and (ii) the group I AIP lactam analogue retains the capacity to activate agr, suggesting that covalent modification of the AgrC receptor is not a necessary prerequisite for agr activation. Although each of the D-amino acid scanned AIP analogues retained activity, replacement of the endocyclic amino acid residue (aspartate) located C-terminally to the, central cysteine with alanine converted the group I AIP from an activator to a potent inhibitor. The screening of clinical S. aureus isolates for novel AIP groups revealed a variant that differed from the group I AIP by a single amino acid residue (aspartate to tyrosine) in the same position defined as critical by alanine scanning. Although this AIP inhibits group I S. aureus strains, the producer strains possess a functional agr locus dependent on the endogenous peptide and, as such, constitute a fourth S. aureus AIP pheromone group (group IV). The addition of exogenous synthetic AIPs to S. aureus inhibited the production of toxic shock syndrome toxin (TSST-1) and enterotoxin C3, confirming the potential of quorum-sensing blockade as a therapeutic strategy.