Antibiotic interactions shape short-term evolution of resistance in E. faecalis.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
19
06
2019
accepted:
11
12
2019
revised:
24
03
2020
pubmed:
3
3
2020
medline:
7
7
2020
entrez:
3
3
2020
Statut:
epublish
Résumé
Antibiotic combinations are increasingly used to combat bacterial infections. Multidrug therapies are a particularly important treatment option for E. faecalis, an opportunistic pathogen that contributes to high-inoculum infections such as infective endocarditis. While numerous synergistic drug combinations for E. faecalis have been identified, much less is known about how different combinations impact the rate of resistance evolution. In this work, we use high-throughput laboratory evolution experiments to quantify adaptation in growth rate and drug resistance of E. faecalis exposed to drug combinations exhibiting different classes of interactions, ranging from synergistic to suppressive. We identify a wide range of evolutionary behavior, including both increased and decreased rates of growth adaptation, depending on the specific interplay between drug interaction and drug resistance profiles. For example, selection in a dual β-lactam combination leads to accelerated growth adaptation compared to selection with the individual drugs, even though the resulting resistance profiles are nearly identical. On the other hand, populations evolved in an aminoglycoside and β-lactam combination exhibit decreased growth adaptation and resistant profiles that depend on the specific drug concentrations. We show that the main qualitative features of these evolutionary trajectories can be explained by simple rescaling arguments that correspond to geometric transformations of the two-drug growth response surfaces measured in ancestral cells. The analysis also reveals multiple examples where resistance profiles selected by drug combinations are nearly growth-optimized along a contour connecting profiles selected by the component drugs. Our results highlight trade-offs between drug interactions and resistance profiles during the evolution of multi-drug resistance and emphasize evolutionary benefits and disadvantages of particular drug pairs targeting enterococci.
Identifiants
pubmed: 32119717
doi: 10.1371/journal.ppat.1008278
pii: PPATHOGENS-D-19-01118
pmc: PMC7093004
doi:
Substances chimiques
Anti-Bacterial Agents
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008278Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM124875
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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