中文摘要：耐多药细菌感染越来越普遍，只有少数抗生素，如粘菌素可用于临床治疗。另一种治疗策略是噬菌体疗法，它具有不受细菌对抗生素耐药性影响的优点。但噬菌体治疗的主要挑战是噬菌体耐药细菌的迅速出现。本研究旨在了解最重要的病原体，鲍曼不动杆菌，对噬菌体的耐药机制。分离出能感染鲍曼不动杆菌的粘菌素敏感和耐药菌株的新噬菌体Phab24，与宿主共孵育后，获得了具有基因型和表型特征的噬菌体耐药突变体。利用全基因组测序，鉴定了噬菌体耐药菌株，这些菌株的基因突变在两个水平上改变了细菌包膜的结构：荚膜和外膜。通过吸附试验，确认噬菌体Phab24以细菌荚膜为主要受体，外膜可能作为次要受体。有趣的是，在mellonella感染模型中，噬菌体耐药菌株比亲本菌株的毒性小。最重要的是，在没有抗生素的情况下，即使抗生素耐药机制本身保持不变，但噬菌体耐药细菌对粘菌素的敏感性增加。这种抗生素敏感性的增加是噬菌体耐药机制的直接结果，有可能在临床环境中加以利用。
外文摘要：Multidrug-resistant bacterial infections are becoming increasingly common, with only few last-resort antibiotics such as colistin available for clinical therapy. An alternative therapeutic strategy gaining momentum is phage therapy, which has the advantage of not being affected by bacterial resistance to antibiotics. However, a major challenge in phage therapy is the rapid emergence of phage-resistant bacteria. In this work, our main aim was to understand the mechanisms of phage-resistance used by the top priority pathogen Acinetobacter baumannii. We isolated the novel phage Phab24, capable of infecting colistin-sensitive and -resistant strains of A. baumannii. After co-incubating Phab24 with its hosts, we obtained phage-resistant mutants which were characterized on both genotypic and phenotypic levels. Using whole genome sequencing, we identified phage-resistant strains that displayed mutations in genes that alter the architecture of the bacterial envelope at two levels: the capsule and the outer membrane. Using an adsorption assay, we confirmed that phage Phab24 uses the bacterial capsule as its primary receptor, with the outer membrane possibly serving as the secondary receptor. Interestingly, the phage-resistant isolates were less virulent compared to the parental strains in a Galleria mellonella infection model. Most importantly, we observed that phage-resistant bacteria that evolved in the absence of antibiotics exhibited an increased sensitivity to colistin, even though the antibiotic resistance mechanism per se remained unaltered. This increase in antibiotic sensitivity is a direct consequence of the phage-resistance mechanism, and could potentially be exploited in the clinical setting.
外文关键词：Phage；phage therapy；phage-resistance；phage adsorption；colistin resistance；antibiotic resensitation；virulence
作者：Wang, XQ；Loh, B；Altamirano, FG；Yu, YS；Hua, XT；Leptihn, S
作者单位：Zhejiang Univ；Lishui Univ；Xian Jiaotong Liverpool Univ；Monash Univ；Key Lab Microbial Technol & Bioinformat Zhejiang；Univ Edinburgh
期刊名称：EMERGING MICROBES & INFECTIONS
期刊影响因子：5.776
出版年份：2021
出版刊次：1
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