PNAS:改造噬菌体提升抗生素药效

2009-03-05 admin PNAS
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美国科学家通过对噬菌体进行改造,使其能够抑制细菌对抗生素的耐受性。如果将其与抗生素联合使用,还能杀死目前已存在的对抗生素广泛耐受的细菌。

噬菌体是一类寄生并侵害细菌的病毒,又称细菌病毒。利用感染和杀死细菌的病毒来战胜传染的理念可以追溯到大约100年前。但这种疗法从未曾在西方使用,当抗生素登上历史的舞台,噬菌体疗法更受冷落。

不断有细菌对抗生素产生抗药性,迫使研究人员不断研发新药物来对抗这些细菌。在以前的“噬菌体疗法”中,噬菌体杀死细菌并且释放更多的噬菌体寻找新的宿主,但处于这种直接进攻下的细菌很快会进化并且对噬菌体产生抵抗力。

美国波士顿大学的生物工程学家詹姆斯·柯林斯和其学生狄莫西·鲁通过改造噬菌体使细菌更加脆弱,从而让抗生素更容易奏效。

柯林斯和鲁使用基因工程技术改造了一个名叫M13的噬菌体,该噬菌体在感染细菌时,会产生名为lexA3的细菌蛋白,该蛋白可以损害细菌修复受损的DNA的能力。当修改后的M13噬菌体感染细菌,比如大肠埃希氏菌时,它产生lexA3,让大肠埃希氏菌更容易受到损害细菌DNA的药物的攻击。

研究人员发现,噬菌体增加了抗生素沃氟沙星杀死大肠埃希氏菌的能力,即使该细菌对抗生素产生一定的抵抗力也如此。该发现表明,这类噬菌体疗法能够恢复以往已被认为不再起作用的抗生素的活力。

在老鼠身上进行的实验也得到了令人振奋的结论:在遭遇大肠埃希氏菌感染时,接受了沃氟沙星和修改后的M13噬菌体的老鼠,有80%%存活下来,而仅仅接受了抗生素的老鼠的存活率只有20%%。

日本高知医学院的松崎重信说:“在控制细菌感染方面,这些发现可能相当重要,但要将其应用于临床实践,还需要一段路要走。”研究人员认为,这项研究为找到对付抗生素耐受性细菌的方法提供了新思路。

原始出处:

PNAS March 2, 2009, doi: 10.1073/pnas.0800442106

Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy

Timothy K. Lua,b and James J. Collinsb,1

aHarvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge, MA 02139; and
bHoward Hughes Medical Institute, Center for BioDynamics and Department of Biomedical Engineering, Boston University, Boston, MA 02215

Antimicrobial drug development is increasingly lagging behind the evolution of antibiotic resistance, and as a result, there is a pressing need for new antibacterial therapies that can be readily designed and implemented. In this work, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly targeted by antibiotics. We show that suppressing the SOS network in Escherichia coli with engineered bacteriophage enhances killing by quinolones by several orders of magnitude in vitro and significantly increases survival of infected mice in vivo. In addition, we demonstrate that engineered bacteriophage can enhance the killing of antibiotic-resistant bacteria, persister cells, and biofilm cells, reduce the number of antibiotic-resistant bacteria that arise from an antibiotic-treated population, and act as a strong adjuvant for other bactericidal antibiotics (e.g., aminoglycosides and β-lactams). Furthermore, we show that engineering bacteriophage to target non-SOS gene networks and to overexpress multiple factors also can produce effective antibiotic adjuvants. This work establishes a synthetic biology platform for the rapid translation and integration of identified targets into effective antibiotic adjuvants.