Resistance to bacteriophage incurs a cost to virulence in drug-resistant Acinetobacter baumannii

Author:

Manley Robyn1ORCID,Fitch Christian1,Francis Vanessa1,Temperton Isaac1,Turner Dann2,Fletcher Julie1,Phil Mitchelmore3,Michell Steve1,Temperton Ben1

Affiliation:

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

2. 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

3. University of Exeter, College of Medicine and Health, Department of Respiratory Medicine, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK

Abstract

Introduction . Acinetobacter baumannii 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. A. baumannii is thus a priority target for phage therapeutics. Two strains of a novel, virulent bacteriophage (LemonAid and Tonic) able to infect carbapenem-resistant A. baumannii (strain NCTC 13420), were isolated from environmental water samples collected through a citizen science programme. Gap statement. 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. Methodology. In vitro and in vivo 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 A. baumannii. Results. A. baumannii 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 Galleria mellonella larval in vivo model. A replicated 8 bp insertion increased in frequency (~40 % higher frequency than in the wild-type) within phage-resistant A. baumannii 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 A. baumannii. We find no evidence linking resistance to changes in capsule structure, a known virulence factor. LemonAid efficiently suppressed growth of A. baumanni in vitro across a wide range of titres. However, in vivo, while survival of A. baumannii infected larvae significantly increased with both remedial and prophylactic treatment with LemonAid (107 p.f.u. ml–1), the effect was weak and not sufficient to save larvae from morbidity and mortality. Conclusion. While LemonAid and Tonic did not prove effective as a treatment in a Galleria larvae model, there is potential to harness their ability to attenuate virulence in drug-resistant A. baumannii.

Funder

GW4 BIOMED MRC DTP

Medical Research Council

Wellcome

Publisher

Microbiology Society

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