Temperate phage-antibiotic synergy is widespread-extending to Pseudomonas-but varies by phage, host strain, and antibiotic pairing.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY
mBio Pub Date : 2024-12-20 DOI:10.1128/mbio.02559-24
Rabia Fatima, Alexander P Hynes
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引用次数: 0

Abstract

Bacteriophages (phages) are bacterial-specific viruses that can be used alone or with antibiotics to reduce bacterial load. Most phages are unsuitable for therapy because they are "temperate" and can integrate into the host genome, forming a lysogen that is protected from subsequent phage infections. However, integrated phages can be awakened by stressors such as antibiotics. Supported by this interaction, here we explore the potential use of combined temperate phage and antibiotic against the multi-drug-resistant pathogen, Pseudomonas aeruginosa. In all, thirty-nine temperate phages were isolated from clinical strains, and a subset was screened for synergy with six antibiotics (ciprofloxacin, levofloxacin, meropenem, piperacillin, tobramycin, and polymyxin B), using checkerboard assays. Interestingly, our screen identified phages that can synergize with each antibiotic, despite their widely differing targets; however, these are highly phage-antibiotic and phage-host pairing specific. Screening across multiple clinical strains reveals that temperate phages can reduce the antibiotic minimum inhibitory concentration up to 32-fold, even in a resistant isolate, functionally re-sensitizing the bacterium to the antibiotic. Meropenem and tobramycin did not reduce the frequency of lysogens, suggesting a mechanism of action independent of the temperate nature of the phages. By contrast, ciprofloxacin and piperacillin were able to reduce the frequency of lysogeny, the former by inducing phages-as previously reported in E. coli. Curiously, synergy with piperacillin reduced lysogen survivors, but not by inducing the phages, suggesting an alternative mechanism for biasing the phage lysis-lysogeny equilibrium. Overall, our findings indicate that temperate phages can act as adjuvants in clinically relevant pathogens, even in the presence of antibiotic resistance, thereby drastically expanding their therapeutic potential.

Importance: The recent discovery that otherwise therapeutically unusable temperate phages can potentiate the activity of antibiotics, resulting in a potent synergy, has only been tested in E. coli, and with a single model phage. Here, working with clinical isolates of Pseudomonas and phages from these isolates, we highlight the broad applicability of this synergy-across a variety of mechanisms but also highlight the limitations of predicting the phage, host, and antibiotic combinations that will synergize.

噬菌体(噬菌体)是细菌特异性病毒,可单独使用或与抗生素一起使用,以减少细菌负荷。大多数噬菌体不适合用于治疗,因为它们 "性情温和",可以整合到宿主基因组中,形成溶菌酶原,免受噬菌体的后续感染。然而,整合后的噬菌体会被抗生素等压力源唤醒。在这种相互作用的支持下,我们在此探讨了结合温带噬菌体和抗生素来对付多重耐药病原体铜绿假单胞菌的潜在用途。我们从临床菌株中总共分离出了 39 个温带噬菌体,并使用棋盘试验筛选了其中一个子集与六种抗生素(环丙沙星、左氧氟沙星、美罗培南、哌拉西林、妥布霉素和多粘菌素 B)的协同作用。有趣的是,尽管每种抗生素的作用靶点大不相同,但我们的筛选发现了能与每种抗生素协同作用的噬菌体;不过,这些噬菌体与抗生素和噬菌体与宿主配对具有高度的特异性。对多种临床菌株的筛选显示,温带噬菌体能将抗生素的最小抑菌浓度降低达 32 倍,即使在耐药分离株中也是如此,从而在功能上使细菌对抗生素重新敏感。美罗培南和妥布霉素并不能降低溶菌酶的频率,这表明其作用机制与噬菌体的温和性无关。相比之下,环丙沙星和哌拉西林能够降低溶菌酶的频率,前者是通过诱导噬菌体来降低溶菌酶的频率,这在大肠杆菌中已有报道。奇怪的是,与哌拉西林的协同作用减少了溶菌酶的存活率,但却没有诱导噬菌体,这表明噬菌体的溶解-溶菌酶平衡存在另一种偏差机制。总之,我们的研究结果表明,即使存在抗生素耐药性,温带噬菌体也能作为佐剂作用于临床相关的病原体,从而极大地拓展了它们的治疗潜力:最近发现,原本不能用于治疗的温带噬菌体可以增强抗生素的活性,从而产生强大的协同作用,但这一发现只在大肠杆菌中进行过测试,而且只使用了一种模型噬菌体。在这里,我们利用假单胞菌的临床分离物和这些分离物中的噬菌体,强调了这种协同作用的广泛适用性--跨越各种机制,但也强调了预测噬菌体、宿主和抗生素组合能产生协同作用的局限性。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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