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Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.

ABSTRACT: Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections.

SUBMITTER: Nguyen D

PROVIDER: S-EPMC4046891 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.

Nguyen Dao D Joshi-Datar Amruta A Lepine Francois F Bauerle Elizabeth E Olakanmi Oyebode O Beer Karlyn K McKay Geoffrey G Siehnel Richard R Schafhauser James J Wang Yun Y Britigan Bradley E BE Singh Pradeep K PK

Science (New York, N.Y.) 20111101 6058

Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), a ...[more]

PMID: 22096200

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Project description:Drosophila melanogaster gut microbes play important roles in host nutritional physiology. However, these associations are often indirect, and studies typically are in the context of specialized nutritional conditions, making it difficult to discern how microbiome-mediated impacts translate to physiologically relevant conditions, in the laboratory or nature. In this study, we quantified changes in dietary nutrients due to D. melanogaster gut bacteria on three artificial diets and a natural diet of grapes. We show that under all four diet conditions, bacteria altered the protein, carbohydrates, and moisture of the food substrate. An in-depth analysis of one diet revealed that bacteria also increased the levels of tryptophan, an essential amino acid encountered scarcely in nature. These nutrient changes result in an increased protein-to-carbohydrate (P:C) ratio in all diets, which we hypothesized to be a significant determinant of microbiome-mediated host nutritional physiology. To test this, we compared life history traits of axenic flies reared on the three artificial diets with increased P:C ratios or continuous bacterial inoculation. We found that while on some diets, an environment of nutritional plenitude had impacts on life history, it did not fully explain all microbiome-associated phenotypes. This suggests that other factors, such as micronutrients and feeding behavior, likely also contribute to life history traits in a diet-dependent manner. Thus, while some bacterial impacts on nutrition occur across diets, others are dictated by unique dietary environments, highlighting the importance of diet-microbiome interactions in D. melanogaster nutritional physiology.IMPORTANCE Both in the laboratory and in nature, D. melanogaster-associated microbes serve as nutritional effectors, either through the production of metabolites or as direct sources of protein biomass. The relationship between the microbiome and the resulting host nutritional physiology is significantly impacted by diet composition, yet studies involving D. melanogaster are performed using a wide range of artificial diets, making it difficult to discern which aspects of host-microbe interactions may be universal or diet dependent. In this study, we utilized three standard D. melanogaster diets and a natural grape diet to form a comprehensive understanding of the quantifiable nutritional changes mediated by the host microbial community. We then altered these artificial diets based on the observed microbe-mediated changes to demonstrate their potential to influence host physiology, allowing us to identify nutritional factors whose effects were either universal for the three artificial diets or dependent on host diet composition.

Dataset Information

Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.

Publications

Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.

Similar Datasets

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