Selective bacteriophages reduce the emergence of resistant bacteria in the bacteriophage-antibiotic combination therapy
Selective bacteriophages reduce the emergence of resistant bacteria in the bacteriophage-antibiotic combination therapy
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选择性噬菌体减少噬菌体-抗生素联合疗法中耐药细菌的出现
DOI：
10.1101/2023.01.22.525106
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Kiga Kotaro
中科院分区：
文献类型：
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作者：
Azam Aa Haeruman;Sato Koji;Miyanaga Kazuhiko;Nakamura Tomohiro;Ojima Shinjiro;Kondo Kohei;Tamura Azumi;Yamashita Wakana;Tanji Yasunori;Kiga Kotaro
大肠杆菌O157：H7是一种重要的食源性致病菌，对食品安全具有重要意义。O157的抗生素治疗可能会导致溶血性尿毒综合征的恶化，并且耐药菌株的流行率越来越高，需要开发新的治疗策略。在这项研究中，抗生素和噬菌体单药治疗的杀菌效果和耐药性的发展进行了比较，对O157的联合治疗。涉及O157连续暴露于磷霉素和抗生素的实验，沿着遗传缺失研究，显示glp和duphpT的缺失显著增加了对磷霉素的抗性。此外，我们发现OmpC作为PP01噬菌体的受体，其感染O157，FhuA作为新分离的SP15噬菌体的受体，靶向O157。在glpTanduhpT缺失突变体中，PP01噬菌体的受体ompC的额外缺失增加了对磷霉素的抗性。这些研究结果表明，特定的噬菌体可能有助于抗生素耐药性的选择，负责噬菌体和抗生素耐药性的基因突变的出现。虽然与磷霉素和抗生素的联合治疗有望治疗细菌感染，噬菌体选择的仔细考虑是necessary. IMPORTANCEThe磷霉素和噬菌体againstEscherichia coliO 157的联合治疗表现出上级杀菌效果相比，单一疗法，有效地抑制了耐药性的出现。然而，由噬菌体PP01选择的突变导致不仅对噬菌体而且对磷霉素的抗性增强。这些发现强调了在选择联合治疗的抗生素时谨慎的重要性，因为特定抗生素选择的耐药性可能会增加抗生素耐药性的风险。
Escherichia coliO157:H7 is a globally important foodborne pathogen with implications for food safety. Antibiotic treatment for O157 may potentially contribute to the exacerbation of hemolytic uremic syndrome, and the increasing prevalence of antibiotic-resistant strains necessitates the development of new treatment strategies. In this study, the bactericidal effects and resistance development of antibiotic and bacteriophage monotherapy were compared with those of combination therapy against O157. Experiments involving continuous exposure of O157 to phages and antibiotics, along with genetic deletion studies, revealed that the deletion ofglpTanduhpTsignificantly increased resistance to fosfomycin. Furthermore, we found that OmpC functions as a receptor for the PP01 phage, which infects O157, and FhuA functions as a receptor for the newly isolated SP15 phage, targeting O157. In theglpTanduhpTdeletion mutants, additional deletion inompC, the receptor for the PP01 phage, increased resistance to fosfomycin. These findings suggest that specific phages may contribute to antibiotic resistance by selecting the emergence of gene mutations responsible for both phage and antibiotic resistance. While combination therapy with phages and antibiotics holds promise for the treatment of bacterial infections, careful consideration of phage selection is necessary.IMPORTANCEThe combination treatment of fosfomycin and bacteriophages againstEscherichia coliO157 demonstrated superior bactericidal efficacy compared to monotherapy, effectively suppressing the emergence of resistance. However, mutations selected by phage PP01 led to enhanced resistance not only to the phage but also to fosfomycin. These findings underscore the importance of exercising caution in selecting phages for combination therapy, as resistance selected by specific phages may increase the risk of developing antibiotic resistance.