Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity
Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicity
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DOI：
10.1073/pnas.1222706110
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发表时间：
2013-04-30
影响因子：
11.1
通讯作者：
Visca, Paolo
中科院分区：
文献类型：
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作者：
Imperi, Francesco;Massai, Francesco;Visca, Paolo
尽管抗生素耐药性代表了一种公共卫生紧急情况，但新抗生素的管道正在枯竭。将旧药物重新用于新的临床应用是药物开发的一个有吸引力的策略。我们使用细菌病原体铜绿假单胞菌作为靶点，用于在市售药物中筛选抗毒力活性。我们发现抗霉菌剂氟胞嘧啶抑制铁饥饿σ因子PvdS的表达，从而抑制主要铜绿假单胞菌毒力因子，即绿脓菌荧光素、PrpL蛋白酶和外毒素A的产生。在肺部感染小鼠模型中，以具有临床意义的给药方案给予氟胞嘧啶可抑制铜绿假单胞菌的致病性。氟胞嘧啶对铜绿假单胞菌的体外和体内活性，结合其理想的药理学特性，为氟胞嘧啶在人体中抗铜绿假单胞菌功效的临床试验铺平了道路。
Although antibiotic resistance represents a public health emergency, the pipeline of new antibiotics is running dry. Repurposing of old drugs for new clinical applications is an attractive strategy for drug development. We used the bacterial pathogen Pseudomonas aeruginosa as a target for the screening of antivirulence activity among marketed drugs. We found that the antimycotic agent flucytosine inhibits the expression of the iron-starvation sigma-factor PvdS, thereby repressing the production of major P. aeruginosa virulence factors, namely pyoverdine, PrpL protease, and exotoxin A. Flucytosine administration at clinically meaningful dosing regimens suppressed P. aeruginosa pathogenicity in a mouse model of lung infection. The in vitro and in vivo activity of flucytosine against P. aeruginosa, combined with its desirable pharmacological properties, paves the way for clinical trials on the anti-P. aeruginosa efficacy of flucytosine in humans.