Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community

Robert E. Beardmore, Emily Cook, Susanna Nilsson, Adam R. Smith, Anna Tillmann, Brooke D. Esquivel, Ken Haynes, Neil A. R. Gow, Alistair J. P. Brown, Theodore C. White, Ivana Gudelj

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Abstract

Microbes rarely exist in isolation, rather, they form intricate multi-species communities that colonize our bodies and inserted medical devices. However, the efficacy of antimicrobials is measured in clinical laboratories exclusively using microbial monocultures. Here, to determine how multi-species interactions mediate selection for resistance during antibiotic treatment, particularly following drug withdrawal, we study a laboratory community consisting of two microbial pathogens. Single-species dose responses are a poor predictor of community dynamics during treatment so, to better understand those dynamics, we introduce the concept of a dose-response mosaic, a multi-dimensional map that indicates how species’ abundance is affected by changes in abiotic conditions. We study the dose-response mosaic of a two-species community with a ‘Gene × Gene × Environment × Environment’ ecological interaction whereby Candida glabrata, which is resistant to the antifungal drug fluconazole, competes for survival with Candida albicans, which is susceptible to fluconazole. The mosaic comprises several zones that delineate abiotic conditions where each species dominates. Zones are separated by loci of bifurcations and tipping points that identify what environmental changes can trigger the loss of either species. Observations of the laboratory communities corroborated theory, showing that changes in both antibiotic concentration and nutrient availability can push populations beyond tipping points, thus creating irreversible shifts in community composition from drug-sensitive to drug-resistant species. This has an important consequence: resistant species can increase in frequency even if an antibiotic is withdrawn because, unwittingly, a tipping point was passed during treatment.
Original languageEnglish
Pages (from-to)1312-1320
Number of pages9
JournalNature Ecology & Evolution
Volume2
Early online date9 Jul 2018
DOIs
Publication statusPublished - 2018

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antibiotics
dose response
drug
fluconazole
drugs
medical equipment
Candida glabrata
antifungal agents
Candida albicans
antibiotic resistance
nutrient availability
anti-infective agents
microorganisms
loci
pathogens
community dynamics
bifurcation
monoculture
community composition
environmental change

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Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community. / Beardmore, Robert E.; Cook, Emily; Nilsson, Susanna; Smith, Adam R.; Tillmann, Anna; Esquivel, Brooke D.; Haynes, Ken; Gow, Neil A. R.; Brown, Alistair J. P.; White, Theodore C.; Gudelj, Ivana.

In: Nature Ecology & Evolution, Vol. 2, 2018, p. 1312-1320.

Research output: Contribution to journalArticle

Beardmore, RE, Cook, E, Nilsson, S, Smith, AR, Tillmann, A, Esquivel, BD, Haynes, K, Gow, NAR, Brown, AJP, White, TC & Gudelj, I 2018, 'Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community', Nature Ecology & Evolution, vol. 2, pp. 1312-1320. https://doi.org/10.1038/s41559-018-0582-7, https://doi.org/10.1038/s41559-018-0678-0
Beardmore, Robert E. ; Cook, Emily ; Nilsson, Susanna ; Smith, Adam R. ; Tillmann, Anna ; Esquivel, Brooke D. ; Haynes, Ken ; Gow, Neil A. R. ; Brown, Alistair J. P. ; White, Theodore C. ; Gudelj, Ivana. / Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community. In: Nature Ecology & Evolution. 2018 ; Vol. 2. pp. 1312-1320.
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abstract = "Microbes rarely exist in isolation, rather, they form intricate multi-species communities that colonize our bodies and inserted medical devices. However, the efficacy of antimicrobials is measured in clinical laboratories exclusively using microbial monocultures. Here, to determine how multi-species interactions mediate selection for resistance during antibiotic treatment, particularly following drug withdrawal, we study a laboratory community consisting of two microbial pathogens. Single-species dose responses are a poor predictor of community dynamics during treatment so, to better understand those dynamics, we introduce the concept of a dose-response mosaic, a multi-dimensional map that indicates how species’ abundance is affected by changes in abiotic conditions. We study the dose-response mosaic of a two-species community with a ‘Gene × Gene × Environment × Environment’ ecological interaction whereby Candida glabrata, which is resistant to the antifungal drug fluconazole, competes for survival with Candida albicans, which is susceptible to fluconazole. The mosaic comprises several zones that delineate abiotic conditions where each species dominates. Zones are separated by loci of bifurcations and tipping points that identify what environmental changes can trigger the loss of either species. Observations of the laboratory communities corroborated theory, showing that changes in both antibiotic concentration and nutrient availability can push populations beyond tipping points, thus creating irreversible shifts in community composition from drug-sensitive to drug-resistant species. This has an important consequence: resistant species can increase in frequency even if an antibiotic is withdrawn because, unwittingly, a tipping point was passed during treatment.",
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note = "Acknowledgements In memory of our friend and colleague Ken Haynes who sadly passed away on 19th March 2018. Author Correction | Published: 19 September 2018 Author Correction: Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community Robert E. Beardmore, Emily Cook, Susanna Nilsson, Adam R. Smith, Anna Tillmann, Brooke D. Esquivel, Ken Haynes, Neil A. R. Gow, Alistair J. P. Brown, Theodore C. White & Ivana Gudelj Nature Ecology & Evolution (2018) https://doi.org/10.1038/s41559-018-0678-0",
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AU - Gudelj, Ivana

N1 - Acknowledgements In memory of our friend and colleague Ken Haynes who sadly passed away on 19th March 2018. Author Correction | Published: 19 September 2018 Author Correction: Drug-mediated metabolic tipping between antibiotic resistant states in a mixed-species community Robert E. Beardmore, Emily Cook, Susanna Nilsson, Adam R. Smith, Anna Tillmann, Brooke D. Esquivel, Ken Haynes, Neil A. R. Gow, Alistair J. P. Brown, Theodore C. White & Ivana Gudelj Nature Ecology & Evolution (2018) https://doi.org/10.1038/s41559-018-0678-0

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N2 - Microbes rarely exist in isolation, rather, they form intricate multi-species communities that colonize our bodies and inserted medical devices. However, the efficacy of antimicrobials is measured in clinical laboratories exclusively using microbial monocultures. Here, to determine how multi-species interactions mediate selection for resistance during antibiotic treatment, particularly following drug withdrawal, we study a laboratory community consisting of two microbial pathogens. Single-species dose responses are a poor predictor of community dynamics during treatment so, to better understand those dynamics, we introduce the concept of a dose-response mosaic, a multi-dimensional map that indicates how species’ abundance is affected by changes in abiotic conditions. We study the dose-response mosaic of a two-species community with a ‘Gene × Gene × Environment × Environment’ ecological interaction whereby Candida glabrata, which is resistant to the antifungal drug fluconazole, competes for survival with Candida albicans, which is susceptible to fluconazole. The mosaic comprises several zones that delineate abiotic conditions where each species dominates. Zones are separated by loci of bifurcations and tipping points that identify what environmental changes can trigger the loss of either species. Observations of the laboratory communities corroborated theory, showing that changes in both antibiotic concentration and nutrient availability can push populations beyond tipping points, thus creating irreversible shifts in community composition from drug-sensitive to drug-resistant species. This has an important consequence: resistant species can increase in frequency even if an antibiotic is withdrawn because, unwittingly, a tipping point was passed during treatment.

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