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Bioassay-guided evolution of glycosylated macrolide antibiotics in Escherichia coli.

ABSTRACT: Macrolide antibiotics such as erythromycin are clinically important polyketide natural products. We have engineered a recombinant strain of Escherichia coli that produces small but measurable quantities of the bioactive macrolide 6-deoxyerythromycin D. Bioassay-guided evolution of this strain led to the identification of an antibiotic-overproducing mutation in the mycarose biosynthesis and transfer pathway that was detectable via a colony-based screening assay. This high-throughput assay was then used to evolve second-generation mutants capable of enhanced precursor-directed biosynthesis of macrolide antibiotics. The availability of a screen for macrolide biosynthesis in E. coli offers a fundamentally new approach in dissecting modular megasynthase mechanisms as well as engineering antibiotics with novel pharmacological properties.

SUBMITTER: Lee HY

PROVIDER: S-EPMC1790958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Antibiotic resistance represents one of the most pressing concerns facing public health today. While the current antibiotic resistance crisis has been driven primarily by the anthropogenic overuse of antibiotics in human and animal health, recent efforts have revealed several important environmental dimensions underlying this public health issue. Antibiotic resistant (AR) microbes, AR genes, and antibiotics have all been found widespread in natural environments, reflecting the ancient origins of this phenomenon. In addition, modern societal advancements in sanitation engineering (i.e., sewage treatment) have also contributed to the dissemination of resistance, and concerningly, may also be promoting the evolution of resistance to water treatment. This is reflected in the recent characterization of naturalized wastewater strains of Escherichia coli-strains that appear to be adapted to live in wastewater (and meat packing plants). These strains carry a plethora of stress-resistance genes against common treatment processes, such as chlorination, heat, UV light, and advanced oxidation, mechanisms which potentially facilitate their survival during sewage treatment. These strains also carry an abundance of common antibiotic resistance genes, and evidence suggests that resistance to some antibiotics is linked to resistance to treatment (e.g., tetracycline resistance and chlorine resistance). As such, these naturalized E. coli populations may be co-evolving resistance against both antibiotics and water treatment. Recently, extraintestinal pathogenic strains of E. coli (ExPEC) have also been shown to exhibit phenotypic resistance to water treatment, seemingly associated with the presence of various shared genetic elements with naturalized wastewater E. coli. Consequently, some pathogenic microbes may also be evolving resistance to the two most important public health interventions for controlling infectious disease in modern society-antibiotic therapy and water treatment.

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Bioassay-guided evolution of glycosylated macrolide antibiotics in Escherichia coli.

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