Cystic Fibrosis Isolates of Pseudomonas aeruginosa Retain Iron-Regulated Antimicrobial Activity against Staphylococcus aureus through the Action of Multiple Alkylquinolones.
Cystic Fibrosis Isolates of Pseudomonas aeruginosa Retain Iron-Regulated Antimicrobial Activity against Staphylococcus aureus through the Action of Multiple Alkylquinolones.
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DOI：
10.3389/fmicb.2016.01171
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发表时间：
2016
影响因子：
5.2
通讯作者：
Oglesby-Sherrouse AG
中科院分区：
文献类型：
--
作者：
Nguyen AT;Jones JW;Cámara M;Williams P;Kane MA;Oglesby-Sherrouse AG
囊性纤维化（CF）是一种遗传性疾病，使个体易患肺功能障碍和慢性感染。CF患者肺部早期感染金黄色葡萄球菌较为常见，而随着疾病进展，铜绿假单胞菌会占主导地位。铜绿假单胞菌的出现可能取决于该菌分泌的多种2 - 烷基 - 4 -（1H）- 喹诺酮（AQ）的作用。我们最近发现，缺铁会增强对金黄色葡萄球菌的抗菌活性，且这种活性依赖于多种AQ代谢物。其中两种AQ，即假单胞菌喹诺酮信号[PQS；2 - 庚基 - 3 - 羟基 - 4（1H）- 喹诺酮]和2 - 庚基 - 4 - 羟基喹啉（HHQ），是群体感应分子，可激活多种杀菌因子的表达。在此我们首次表明，HHQ对金黄色葡萄球菌也具有天然抗菌活性。我们进一步表明，缺铁增强了HHQ以及2 - 庚基 - 4 - 羟基喹啉 - N - 氧化物（HQNO）（另一种作为细胞色素B抑制剂的AQ）的抗葡萄球菌活性。值得注意的是，我们发现缺失PQS或HQNO末端生物合成步骤的基因会导致HHQ中间产物过量产生，可能维持了这些突变体介导抗菌活性的能力。在PQS缺陷的CF分离株中也观察到HHQ的代偿性增加，这些分离株也保留了介导对金黄色葡萄球菌的铁调节抗菌活性的能力。这些研究表明，铜绿假单胞菌对金黄色葡萄球菌的铁调节抗菌活性是由于多种AQ代谢物的累积效应，其产生和活性均受环境铁水平的调节。
Cystic fibrosis (CF) is a hereditary disease that predisposes individuals to pulmonary dysfunction and chronic infections. Early infection of the CF lung with Staphylococcus aureus is common, while Pseudomonas aeruginosa becomes dominant as disease progresses. Emergence of P. aeruginosa likely depends on the action of multiple 2-alkyl-4-(1H)-quinolones (AQ) secreted by this organism. We recently showed that antimicrobial activity against S. aureus is enhanced by iron depletion and is dependent upon multiple AQ metabolites. Two of these AQs, the Pseudomonas quinolone signal [PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone] and 2-heptyl-4-hydroxyquinoline (HHQ), are quorum sensing molecules that activate the expression of multiple microbicidal factors. Here we show for the first time that HHQ also exhibits innate antimicrobial activity against S. aureus. We further show that iron depletion potentiates the antistaphylococcal activity of HHQ, as well as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), another AQ that functions as a cytochrome B inhibitor. Notably, we found that deletion of the genes for the terminal biosynthetic steps for either PQS or HQNO results in overproduction of the HHQ intermediate, likely maintaining the ability of these mutants to mediate antimicrobial activity. Compensatory increases in HHQ were also observed in PQS-deficient CF isolates, which also retained the ability to mediate iron-regulated antimicrobial activity against S. aureus. These studies demonstrate that iron-regulated antimicrobial activity of P. aeruginosa against S. aureus is due to the cumulative effects of multiple AQ metabolites, both the production and activity of which are modulated by environmental iron levels.