Anastassopoulou Cleo, Tsakri Deny, Panagiotopoulos Antonios-Periklis, Saldari Chrysa, Sagona Antonia P, Tsakris Athanasios
Department of Microbiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
Viruses. 2025 Jun 27;17(7):911. doi: 10.3390/v17070911.
The increasing prevalence of multidrug-resistant (MDR) bacterial infections necessitates the exploration of alternative antimicrobial strategies, with phage therapy emerging as a viable option. However, the effectiveness of naturally occurring phages can be significantly limited by bacterial defense systems that include adsorption blocking, restriction-modification, CRISPR-Cas immunity, abortive infection, and NAD+ depletion defense systems. This review examines these bacterial defenses and their implications for phage therapy, while highlighting the potential of phages' bioengineering to overcome these barriers. By leveraging synthetic biology, genetically engineered phages can be tailored to evade bacterial immunity through such modifications as receptor-binding protein engineering, anti-CRISPR gene incorporation, methylation pattern alterations, and enzymatic degradation of bacterial protective barriers. "Armed phages", enhanced with antimicrobial peptides, CRISPR-based genome-editing tools, or immune-modulating factors, offer a novel therapeutic avenue. Clinical trials of bioengineered phages, currently SNIPR001 and LBP-EC01, showcase their potential to safely and effectively combat MDR infections. SNIPR001 has completed a Phase I clinical trial evaluating safety in healthy volunteers, while LBP-EC01 is in Phase II trials assessing its performance in the treatment of -induced urinary tract infections in patients with a history of drug-resistant infections. As "armed phages" progress toward clinical application, they hold great promise for precision-targeted antimicrobial therapies and represent a critical innovation in addressing the global antibiotic resistance crisis.
多重耐药（MDR）细菌感染的日益普遍使得探索替代抗菌策略成为必要，噬菌体疗法成为一种可行的选择。然而，天然噬菌体的有效性可能会受到细菌防御系统的显著限制，这些防御系统包括吸附阻断、限制修饰、CRISPR-Cas免疫、流产感染和NAD+消耗防御系统。本综述研究了这些细菌防御机制及其对噬菌体疗法的影响，同时强调了噬菌体生物工程克服这些障碍的潜力。通过利用合成生物学，可以对基因工程噬菌体进行定制，通过受体结合蛋白工程、抗CRISPR基因整合、甲基化模式改变以及细菌保护屏障的酶促降解等修饰来逃避细菌免疫。“武装噬菌体”通过抗菌肽、基于CRISPR的基因组编辑工具或免疫调节因子得到增强，提供了一种新的治疗途径。目前，生物工程噬菌体SNIPR001和LBP-EC01的临床试验展示了它们安全有效地对抗MDR感染的潜力。SNIPR001已经完成了一项评估健康志愿者安全性的I期临床试验，而LBP-EC01正在进行II期试验，评估其在治疗有耐药感染史患者的诱导性尿路感染中的表现。随着“武装噬菌体”向临床应用迈进，它们在精准靶向抗菌治疗方面具有巨大潜力，代表了应对全球抗生素耐药危机的一项关键创新。
