耐药 对噬菌体的抗性会导致其毒力降低。

Resistance to bacteriophage incurs a cost to virulence in drug-resistant .

机构信息

University of Exeter, Health and Life Sciences, Streatham Campus, Exeter, EX4 4QD, UK.

School of Applied Sciences, College of Health, Science and Society, University of the West of England, Bristol, Frenchay Campus, Coldharbour Lane, Bristol, BS16 1QY, UK.

出版信息

J Med Microbiol. 2024 May;73(5). doi: 10.1099/jmm.0.001829.

Abstract

is a critical priority pathogen for novel antimicrobials (World Health Organization) because of the rise in nosocomial infections and its ability to evolve resistance to last resort antibiotics. is thus a priority target for phage therapeutics. Two strains of a novel, virulent bacteriophage (LemonAid and Tonic) able to infect carbapenem-resistant (strain NCTC 13420), were isolated from environmental water samples collected through a citizen science programme. Phage-host coevolution can lead to emergence of host resistance, with a concomitant reduction in the virulence of host bacteria; a potential benefit to phage therapy applications. and assays, genomics and microscopy techniques were used to characterize the phages; determine mechanisms and impact of phage resistance on host virulence, and the efficacy of the phages against . developed resistance to both viruses, LemonAid and Tonic. Resistance came at a cost to virulence, with the resistant variants causing significantly reduced mortality in a larval model. A replicated 8 bp insertion increased in frequency (~40 % higher frequency than in the wild-type) within phage-resistant mutants, putatively resulting in early truncation of a protein of unknown function. Evidence from comparative genomics and an adsorption assay suggests this protein acts as a novel phage receptor site in . We find no evidence linking resistance to changes in capsule structure, a known virulence factor. LemonAid efficiently suppressed growth of across a wide range of titres. However, , while survival of infected larvae significantly increased with both remedial and prophylactic treatment with LemonAid (10 p.f.u. ml), the effect was weak and not sufficient to save larvae from morbidity and mortality. While LemonAid and Tonic did not prove effective as a treatment in a larvae model, there is potential to harness their ability to attenuate virulence in drug-resistant .

摘要

是新型抗菌药物的重点病原体(世界卫生组织),因为其院内感染率上升,并且能够对抗最后手段的抗生素产生耐药性。因此,是噬菌体治疗的重点目标。从通过公民科学计划收集的环境水样中分离出两种新型、毒性噬菌体(LemonAid 和 Tonic),能够感染耐碳青霉烯的 (NCTC 13420 株)。噬菌体-宿主共同进化会导致宿主耐药性的出现,同时降低宿主细菌的毒力;这是噬菌体治疗应用的潜在好处。噬菌体-宿主相互作用、基因组学和显微镜技术用于表征噬菌体;确定噬菌体耐药性对宿主毒力的机制和影响,以及噬菌体对 的疗效。 在 中开发出对两种病毒(LemonAid 和 Tonic)的耐药性。耐药性是以毒力为代价的,耐药变体在幼虫模型中导致死亡率显著降低。在噬菌体抗性 突变体中,8 个核苷酸重复插入的频率增加(比野生型高出约 40%),推测导致一种未知功能的蛋白质早期截断。来自比较基因组学和吸附试验的证据表明,该蛋白在 中作为一种新的噬菌体受体位点。我们没有发现耐药性与荚膜结构变化有关的证据,荚膜结构是一种已知的毒力因素。LemonAid 能够有效地抑制 在广泛滴度范围内的生长。然而,尽管在预防性和补救性治疗中,LemonAid(10 p.f.u. ml)显著增加了感染 幼虫的存活率,但效果较弱,不足以使幼虫免受发病和死亡的影响。虽然 LemonAid 和 Tonic 并未在 幼虫模型中证明有效,但有可能利用它们降低耐药性 毒力的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99d0/11170128/783efeac0958/jmm-73-01829-g001.jpg

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