Conclusion and Perspectives
结论与展望
Current challenges facing phage therapy are: compatibility with current quality and safety requirements, necessitating the stability of phage preparations for long periods of time, designing effective assays for phage screening, overcoming the limited activity of phages in biofilms, controlling and disabling the appearance of bacterial resistance to phages, production of antibody-neutralizing phages, sequestration by the spleen and liver, and launching an appropriate regulatory framework for phage products.31,103 A comparison of different antibacterial treatment mechanisms by administering antibiotics and phages is shown in Table 1. The pros and cons of phage therapy are shown in Table 2.
噬菌体疗法目前面临的挑战包括：与当前质量和安全要求的兼容性、噬菌体制剂长期稳定性的必要性、设计噬菌体筛选的有效检测方法、克服噬菌体在生物膜中的有限活性、控制和消除细菌对噬菌体的抗药性、抗体中和噬菌体的产生、脾脏和肝脏的螯合作用以及为噬菌体产品制定适当的监管框架。 31 103 表 1 对施用抗生素和噬菌体的不同抗菌治疗机制进行了比较。噬菌体疗法的利弊见表 2。
Table 1 表 1
Comparison of Antibiotic and Lytic Phage Therapy
抗生素与溶菌噬菌体疗法的比较
| Antibiotics 抗生素 | Lytic Phage 溶菌噬菌体 | Reference(s) 参考文献 | |
|---|---|---|---|
| Mechanism of action 作用机制 | Inhibition of cell-wall synthesis, DNA replication, or protein synthesis 抑制细胞壁合成、DNA 复制或蛋白质合成 | Infection and subsequent lysis of bacteria 细菌的感染和随后的裂解 | [61] [ 61 ] |
| Specificity 特殊性 | (Usually) broad spectrum: Gram-negative or Gram-positive species, or both (通常）广谱：革兰氏阴性或革兰氏阳性菌，或两者兼而有之 | Narrow spectrum: one or many individual strains within a bacterial species 窄谱：细菌种类中的一种或多种菌株 | [54,55] [ 54 , 55] |
| Vital microorganism 重要微生物 | No | Yes (inactivation by heat or low pH) 是（加热或低 pH 值会使其失活） | [16] [ 16 ] |
| Innate immune stimulation 先天性免疫刺激 | No direct effect on innate immune cells 对先天性免疫细胞无直接影响 | Phages contain PAMPs such as DNA and RNA. Release of PAMPs upon loss of bacterial cell-wall integrity, Release of PAMPs upon bacterial cell lysis 噬菌体含有 DNA 和 RNA 等 PAMPs。细菌细胞壁完整性丧失时释放 PAMPs，细菌细胞裂解时释放 PAMPs | [16–18] [ 16–18 ] |
| Ab induction Ab 诱导 | No | Yes (phages are complex biological organisms bearing immunogenic proteins) 是（噬菌体是带有免疫原蛋白的复杂生物有机体） | [19] [ 19 ] |
| Half-life 半衰期 | Several hours up to 1 day 数小时至 1 天 | Depending on host immunity and target species bioburden, hours to weeks 视宿主免疫力和目标物种生物负荷而定，几小时到几周不等 | [16] [ 16 ] |
| Resistance development 抵抗力发展 | Natural resistance (target missing) 自然阻力（目标缺失） | Natural resistance (presence of no susceptible strains) 天然抗药性（不存在易感菌株） | [62] [ 62 ] |
| Acquired resistance (accessory genomic elements encoding resistance mechanisms) 获得性抗药性（编码抗药性机制的附属基因组元件） | Acquired resistance (selection of no susceptible strains based on CRISPR-Cas system, target modification, etc.) 获得性抗药性（基于 CRISPR-Cas 系统、靶标修饰等方法选择无易感菌株） | [63–65] [ 63–65 ] | |
| Development of resistance upon exposure (mutations) 接触后产生抗药性（突变） |
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Table 2 表 2
Pros and Cons of Lytic and Temperate Phage Therapy
溶菌性噬菌体疗法和温性噬菌体疗法的利与弊
| Type of Phage 噬菌体类型 | Pros 优点 | Cons 缺点 |
|---|---|---|
| Temperate phage 温带噬菌体 | Abundant in nature and found in half of sequenced bacteria66 在自然界中含量丰富，在半数测序细菌中发现 66 | Inherent ability to enhance virulence67 增强毒性的固有能力 67 |
| Can be engineered to avoid bacterial lysis68 可设计成避免细菌溶解 68 | Inherent ability to promote antibiotic resistance67 促进抗生素耐药性的固有能力 67 | |
| Can be used as naturally lytic phages or can be improved more12,68 可作为天然裂解噬菌体使用，也可进行更多改进 12 , 68 | No quick bactericidal effect69 无快速杀菌作用 69 | |
| The function of most phage genes is unknown, and they may participate in unwanted or unrecognized activities69 大多数噬菌体基因的功能尚不清楚，它们可能参与了不需要的或未被识别的活动 。 | ||
| Lytic phage 溶菌噬菌体 | More specific4 更具体 4 | Sequestration of phages by spleen and liver, antibody production against phage, narrow host range, poor accessibility of infected tissue at a distance70 噬菌体被脾脏和肝脏封存，产生抗噬菌体的抗体，宿主范围窄，受感染组织不易远距离接触 70 |
| Quick bacterial lysis71,72 细菌快速溶解 71 , 72 | Rapid release of endotoxins due to bacterial cell lysis, emergence of bacterial resistance to phages, potential transfer of genetic material such as virulence factors (VFs) from virulent bacterium to a phage, and potential transfer of pathogenic bacterium acquired genes that code antibiotic resistance through phages to the microbiome are limitations of phage therapy71,72 细菌细胞裂解导致内毒素快速释放、细菌对噬菌体产生抗药性、毒性细菌可能将毒性因子等遗传物质转移到噬菌体、病原菌可能通过噬菌体将获得的编码抗生素抗性的基因转移到微生物组，这些都是噬菌体疗法的局限性 。 | |
| For drug and vaccine delivery71,72 用于药物和疫苗输送 71 , 72 | ||
| Equally effective for sensitive and MDR bacteria9,10 |
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Phage therapy is a promising approach to combat bacterial infections, including multidrug-resistant bacteria. For efficacious phage therapy, phages need to be present in high concentrations, stable, able to encounter bacteria with no restrictions, and able to replicate. Phage therapy can be used either as an alternative or as a supplement to antibiotics. The increment of antibiotic-resistant bacteria can be reduced using phage cocktails, phage-derived lytic proteins, bioengineered phages, and/or antibiotics. Phage therapy is highly specific, effective in lysing the targeted bacteria, safe (as seen in Eastern Europe), and quickly modifiable to fight newly emerging bacterial threats. Although it has been shown to be effective in some clinical trials, many of the trials do not meet the existing high standards for clinical trials and many questions remain regarding the therapeutic use of phages. Better understanding of phage–host and phage–human interactions, phage diversity, phage dynamics, and genome function is essential to develop a new strategy in the fight against bacterial infections and to overcome the challenges associated with phage therapy. Nevertheless, despite numerous studies having been conducted on phage therapy in the last few decades in the Western world, and before that in Eastern Europe, no phage therapies for humans have been approved by the European Union or the US FDA. Finally, further all-inclusive intensive studies are necessary to justify phage therapy for large-scale clinical use.
噬菌体疗法是一种很有前景的抗击细菌感染（包括耐多药细菌）的方法。要实现有效的噬菌体疗法，噬菌体必须具有高浓度、稳定、不受限制地与细菌相遇并能复制等特点。噬菌体疗法既可以作为抗生素的替代品，也可以作为抗生素的补充。使用噬菌体鸡尾酒、噬菌体衍生的溶菌蛋白、生物工程噬菌体和/或抗生素可以减少抗生素耐药细菌的增量。噬菌体疗法具有高度特异性，能有效溶解目标细菌，安全可靠（如在东欧所见），并可快速修改以应对新出现的细菌威胁。虽然噬菌体疗法在一些临床试验中被证明是有效的，但许多试验并不符合现有的临床试验高标准，而且在噬菌体的治疗用途方面仍存在许多问题。更好地了解噬菌体-宿主和噬菌体-人类之间的相互作用、噬菌体多样性、噬菌体动态和基因组功能，对于开发抗击细菌感染的新策略和克服与噬菌体疗法相关的挑战至关重要。然而，尽管过去几十年来西方世界和东欧国家对噬菌体疗法进行了大量研究，但欧盟和美国食品和药物管理局尚未批准任何用于人类的噬菌体疗法。最后，要证明噬菌体疗法可用于大规模临床治疗，还需要进一步开展全面深入的研究。