Streptococcus mitis and S. oralis lack a requirement for CdsA, the enzyme required for synthesis of major membrane phospholipids in bacteria.

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2017-02-21

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Abstract

Synthesis and integrity of the cytoplasmic membrane is fundamental to cellular life. Experimental evolution studies have hinted at unique physiology in the Gram-positive bacteria Streptococcus mitis and S. oralis These organisms commonly cause bacteremia and infectious endocarditis (IE) but are rarely investigated in mechanistic studies of physiology and evolution. Unlike other Gram-positive pathogens, high-level (MIC ≥ 256 μg/mL) daptomycin resistance rapidly emerges in S. mitis and S. oralis after a single drug exposure. In this study, we find that inactivating mutations in cdsA are associated with high-level daptomycin resistance in S. mitis and S. oralis IE isolates. This is surprising given that cdsA is an essential gene for life in commonly studied model organisms. CdsA encodes the enzyme responsible for the synthesis of cytidine diphosphate-diacylglycerol, a key intermediate for the biosynthesis of all major phospholipids in prokaryotes and most anionic phospholipids in eukaryotes. Lipidomic analysis by liquid chromatography/mass spectrometry (LC/MS) showed that daptomycin-resistant strains have an accumulation of phosphatidic acid and completely lack phosphatidylglycerol and cardiolipin, two major anionic phospholipids in wild-type strains, confirming the loss-of-function of CdsA in the daptomycin-resistant strains. To our knowledge, these daptomycin-resistant streptococci represent the first model organisms whose viability is CdsA-independent. The distinct membrane compositions resulting from the inactivation of cdsA not only provide novel insights into the mechanisms of daptomycin resistance, but also offer unique opportunities to study the physiological functions of major anionic phospholipids in bacteria.

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10.1128/AAC.02552-16

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Adams, Hannah M, Luke R Joyce, Ziqiang Guan, Ronda L Akins and Kelli L Palmer (2017). Streptococcus mitis and S. oralis lack a requirement for CdsA, the enzyme required for synthesis of major membrane phospholipids in bacteria. Antimicrob Agents Chemother. 10.1128/AAC.02552-16 Retrieved from https://hdl.handle.net/10161/14220.

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Guan

Ziqiang Guan

Research Professor in Biochemistry

We develop and apply mass spectrometry techniques to address biochemical and biomedical questions that are lipid-related. Research projects include:

1) Structural lipidomics

o   Develop and apply high resolution tandem mass spectrometry-based lipidomics for the discovery, structural elucidation and functional study of novel lipids.

2) Elucidation of novel pathways/enzymes of lipid biosynthesis and metabolism

o   Genetic, biochemical and MS approaches are employed to identify the substrates and pathways involved in lipid biosynthesis and metabolism

3) Identification of lipid biomarkers of genetic diseases and cancers

o    Provide molecular insights into the disease mechanisms, as well as to serve as the diagnostic and prognostic tools of diseases.


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