Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence.
Raloxifene attenuates Pseudomonas aeruginosa pyocyanin production and virulence.
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DOI：
10.1016/j.ijantimicag.2012.05.009
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发表时间：
2012-09
影响因子：
10.8
通讯作者：
Brinkman FS
中科院分区：
文献类型：
--
作者：
Ho Sui SJ;Lo R;Fernandes AR;Caulfield MD;Lerman JA;Xie L;Bourne PE;Baillie DL;Brinkman FS
通过使用“抗感染”药物来破坏细菌毒力机制作为感染性疾病控制的一种形式，已经引起了越来越大的兴趣。铜绿假单胞菌是一种机会致病菌，以其固有的抗生素耐药性而闻名，可导致严重感染，需要新的治疗选择。在这项研究中，铜绿假单胞菌PAO 1推导的蛋白质组进行分析，以确定病原体相关蛋白。然后使用计算筛选方法来发现药物再利用的机会，即鉴定结合并可能破坏病原体相关蛋白靶点的批准药物。选择性雌激素受体调节剂雷洛昔芬，目前用于预防绝经后妇女的骨质疏松症和/或浸润性乳腺癌的药物，预测从该筛选结合铜绿假单胞菌PhzB 2。PhzB 2参与通过吩嗪生物合成途径产生的蓝色色素绿脓菌素的产生。绿脓菌素对真核细胞有毒，并且已被证明在小鼠模型的感染中发挥作用，使其成为抗感染药物发现的有吸引力的靶点。在秀丽隐杆线虫感染模型中，雷洛昔芬可显著减弱铜绿假单胞菌的毒力。用雷洛昔芬处理铜绿假单胞菌野生型菌株PAO 1和PA 14导致体外绿脓菌素产量呈剂量依赖性降低; phzB 2插入突变体的绿脓菌素产量和毒力也降低。这些结果表明，雷洛昔芬可能适合进一步开发作为铜绿假单胞菌感染的治疗药物，并且这些已经批准的药物可以通过计算筛选并可能重新用作新型抗感染/抗毒力药物。
There has been growing interest in disrupting bacterial virulence mechanisms as a form of infectious disease control through the use of ‘anti-infective’ drugs. Pseudomonas aeruginosa is an opportunistic pathogen noted for its intrinsic antibiotic resistance that causes serious infections requiring new therapeutic options. In this study, an analysis of the P. aeruginosa PAO1 deduced proteome was performed to identify pathogen-associated proteins. A computational screening approach was then used to discover drug repurposing opportunities, i.e. identifying approved drugs that bind and potentially disrupt the pathogen-associated protein targets. The selective oestrogen receptor modulator raloxifene, a drug currently used in the prevention of osteoporosis and/or invasive breast cancer in post-menopausal women, was predicted from this screen to bind P. aeruginosa PhzB2. PhzB2 is involved in production of the blue pigment pyocyanin produced via the phenazine biosynthesis pathway. Pyocyanin is toxic to eukaryotic cells and has been shown to play a role in infection in a mouse model, making it an attractive target for anti-infective drug discovery. Raloxifene was found to strongly attenuate P. aeruginosa virulence in a Caenorhabditis elegans model of infection. Treatment of P. aeruginosa wild-type strains PAO1 and PA14 with raloxifene resulted in a dose-dependent reduction in pyocyanin production in vitro; pyocyanin production and virulence were also reduced for a phzB2 insertion mutant. These results suggest that raloxifene may be suitable for further development as a therapeutic for P. aeruginosa infection and that such already approved drugs may be computationally screened and potentially repurposed as novel anti-infective/anti-virulence agents.
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影响因子：
7
作者：
Lewenza, S;Falsafi, RK;Hancock, REW
通讯作者：
Hancock, REW
影响因子：
3.2
作者：
ESSAR, DW;EBERLY, L;CRAWFORD, IP
通讯作者：
CRAWFORD, IP
影响因子：
3.2
作者：
Mavrodi, DV;Bonsall, RF;Thomashow, LS
通讯作者：
Thomashow, LS
基因组分析表明，铜绿假单胞菌的毒力是组合。
影响因子：
12.3
作者：
Lee DG;Urbach JM;Wu G;Liberati NT;Feinbaum RL;Miyata S;Diggins LT;He J;Saucier M;Déziel E;Friedman L;Li L;Grills G;Montgomery K;Kucherlapati R;Rahme LG;Ausubel FM
通讯作者：
Ausubel FM
影响因子：
4.2
作者：
Fothergill JL;Panagea S;Hart CA;Walshaw MJ;Pitt TL;Winstanley C
通讯作者：
Winstanley C