最近证明了温带噬菌体和抗生素环丙沙星之间的协同作用,这表明了一种可扩展的方法来利用温带噬菌体进行治疗。称为温和的噬菌体-抗生素协同作用,它特别与裂解-溶源决策相互作用。为了确定这是否适用于抗生素,我们用噬菌体HK97和一组共7类的13种抗生素挑战大肠杆菌。不出所料,考虑到保守的诱导途径,我们观察到与已知诱导SOS反应的药物的协同作用:磺胺类药物,其他喹诺酮类药物,和丝裂霉素C。虽然一些β-内酰胺表现出协同作用,这似乎是传统的噬菌体-抗生素协同作用,对裂解-溶源性决定没有影响。奇怪的是,我们观察到与未知的诱导SOS反应的抗生素的有效协同作用:蛋白质合成抑制剂庆大霉素,卡那霉素,四环素,和阿奇霉素.协同作用导致庆大霉素的有效最小抑制浓度降低八倍,彻底根除细菌,and,当以次优剂量给药时,大大降低了从联合挑战中出现的溶菌原的频率。然而,溶原对抗生素的敏感性没有增加;在没有RecA的情况下保持了协同作用;抗生素降低了溶源的初始频率,而不是针对形成的溶原进行选择。我们的结果证实,诱导SOS的抗生素广泛导致温和的噬菌体特异性协同作用,但是其他抗生素可以与温带噬菌体特异性相互作用并产生协同作用。这是关于化学阻断进入溶源的方法的第一份报告,为操纵关键裂解-溶源决策提供了新的手段。重要因素大多数细菌病毒(噬菌体,噬菌体),决定是杀死他们的宿主还是在其中休眠。超过一半的含有噬菌体的细菌等待醒来,这是所有生物学中最重要的行为之一。由于这种行为,这些噬菌体也被认为无法用于治疗。在本文中,我们发现许多抗生素偏袒这种行为“唤醒”休眠噬菌体,迫使他们杀死他们的宿主,但有些人也会首先防止休眠。这些将是研究这一关键决策点的重要工具,并可能使这些噬菌体的治疗用途成为可能。
A recent demonstration of synergy between a temperate phage and the antibiotic ciprofloxacin suggested a scalable approach to exploiting temperate phages in therapy, termed temperate phage-antibiotic synergy, which specifically interacted with the lysis-lysogeny decision. To determine whether this would hold true across antibiotics, we challenged Escherichia coli with the phage HK97 and a set of 13 antibiotics spanning seven classes. As expected, given the conserved induction pathway, we observed synergy with classes of drugs known to induce an SOS response: a sulfa drug, other quinolones, and mitomycin C. While some β-lactams exhibited synergy, this appeared to be traditional phage-antibiotic synergy, with no effect on the lysis-lysogeny decision. Curiously, we observed a potent synergy with antibiotics not known to induce the SOS response: protein synthesis inhibitors gentamicin, kanamycin, tetracycline, and azithromycin. The synergy results in an eightfold reduction in the effective minimum inhibitory concentration of gentamicin, complete eradication of the bacteria, and, when administered at sub-optimal doses, drastically decreases the frequency of lysogens emerging from the combined challenge. However, lysogens exhibit no increased sensitivity to the antibiotic; synergy was maintained in the absence of RecA; and the antibiotic reduced the initial frequency of lysogeny rather than selecting against formed lysogens. Our results confirm that SOS-inducing antibiotics broadly result in temperate-phage-specific synergy, but that other antibiotics can interact with temperate phages specifically and result in synergy. This is the first report of a means of chemically blocking entry into lysogeny, providing a new means for manipulating the key lysis-lysogeny decision.IMPORTANCEThe lysis-lysogeny decision is made by most bacterial viruses (bacteriophages, phages), determining whether to kill their host or go dormant within it. With over half of the bacteria containing phages waiting to wake, this is one of the most important behaviors in all of biology. These phages are also considered unusable for therapy because of this behavior. In this paper, we show that many antibiotics bias this behavior to \"wake\" the dormant phages, forcing them to kill their host, but some also prevent dormancy in the first place. These will be important tools to study this critical decision point and may enable the therapeutic use of these phages.