Decolonizing drug-resistant E. coli with phage and probiotics: breaking the frequency-dependent dominance of residents

Author:

Forsyth Jessica H.12,Barron Natalie L.2,Scott Lucy2,Watson Bridget N. J.2ORCID,Chisnall Matthew A. W.2,Meaden Sean32,van Houte Stineke2ORCID,Raymond Ben2ORCID

Affiliation:

1. Present address: Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK

2. Centre for Ecology and Conservation, University of Exeter, Penryn, TR10 9FE, UK

3. Present address: Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK

Abstract

Widespread antibiotic resistance in commensal bacteria creates a persistent challenge for human health. Resident drug-resistant microbes can prevent clinical interventions, colonize wounds post-surgery, pass resistance traits to pathogens or move to more harmful niches following routine interventions such as catheterization. Accelerating the removal of resistant bacteria or actively decolonizing particular lineages from hosts could therefore have a number of long-term benefits. However, removing resident bacteria via competition with probiotics, for example, poses a number of ecological challenges. Resident microbes are likely to have physiological and numerical advantages and competition based on bacteriocins or other secreted antagonists is expected to give advantages to the dominant partner, via positive frequency dependence. Since a narrow range of Escherichia coli genotypes (primarily those belonging to the clonal group ST131) cause a significant proportion of multidrug-resistant infections, this group presents a promising target for decolonization with bacteriophage, as narrow-host-range viral predation could lead to selective removal of particular genotypes. In this study we tested how a combination of an ST131-specific phage and competition from the well-known probiotic E. coli Nissle strain could displace E. coli ST131 under aerobic and anaerobic growth conditions in vitro. We showed that the addition of phage was able to break the frequency-dependent advantage of a numerically dominant ST131 isolate. Moreover, the addition of competing E. coli Nissle could improve the ability of phage to suppress ST131 by two orders of magnitude. Low-cost phage resistance evolved readily in these experiments and was not inhibited by the presence of a probiotic competitor. Nevertheless, combinations of phage and probiotic produced stable long-term suppression of ST131 over multiple transfers and under both aerobic and anaerobic growth conditions. Combinations of phage and probiotic therefore have real potential for accelerating the removal of drug-resistant commensal targets.

Funder

Medical Research Council

Biotechnology and Biological Sciences Research Council

Lister Institute of Preventive Medicine

Publisher

Microbiology Society

Subject

Microbiology

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