Clostridium difficile contains plasmalogen species of phospholipids and glycolipids

Guan, Ziqiang; Katzianer, David S.; Zhu, Jun; Goldfine, Howard

doi:10.1016/j.bbalip.2014.06.011

Cited by 35 publications

(60 citation statements)

References 21 publications

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“…C. difficile 630 produces phosphatidylglycerol, cardiolipin, and monohexosyldiradylglycerol lipids of both plasmalogen and di-or tetra-acyl forms (55). The relative ratios of these lipids are likely to impact C. difficile membrane fluidity, and the ratios may change in response to fluctuations in growth environment or in times of stress (55). Whether these lipids are differentially distributed in the C. difficile membrane is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…The surR gene is divergently transcribed from CD1344, which encodes a predicted diacylglycerol glucosyltransferase (PRK13609; E value, 9.67e Ϫ49 ). Because C. difficile 630 produces a number of glycolipids (55), this provides a potential link between SurR and membrane structure and biogenesis. Global gene expression comparisons between the Cdi2994 parent and pass strains as well as specific investigation of the CD1344 gene would be of interest for future studies.…”

Section: Resultsmentioning

confidence: 99%

“…First, the membrane structure of C. difficile appears to be distinct. C. difficile 630, like other clostridia (74), possesses membrane phospholipids with plasmalogen (having an ether, instead of ester, linkage at the sn-1 position of glycerol) fatty acid tails (55). C. difficile 630 produces phosphatidylglycerol, cardiolipin, and monohexosyldiradylglycerol lipids of both plasmalogen and di-or tetra-acyl forms (55).…”

Section: Resultsmentioning

confidence: 99%

“…C. difficile 630, like other clostridia (74), possesses membrane phospholipids with plasmalogen (having an ether, instead of ester, linkage at the sn-1 position of glycerol) fatty acid tails (55). C. difficile 630 produces phosphatidylglycerol, cardiolipin, and monohexosyldiradylglycerol lipids of both plasmalogen and di-or tetra-acyl forms (55). The relative ratios of these lipids are likely to impact C. difficile membrane fluidity, and the ratios may change in response to fluctuations in growth environment or in times of stress (55).…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Adams

Mascio

et al. 2015

Antimicrob Agents Chemother

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bClostridium difficile infection (CDI) is an urgent public health concern causing considerable clinical and economic burdens. CDI can be treated with antibiotics, but recurrence of the disease following successful treatment of the initial episode often occurs. Surotomycin is a rapidly bactericidal cyclic lipopeptide antibiotic that is in clinical trials for CDI treatment and that has demonstrated superiority over vancomycin in preventing CDI relapse. Surotomycin is a structural analogue of the membraneactive antibiotic daptomycin. Previously, we utilized in vitro serial passage experiments to derive C. difficile strains with reduced surotomycin susceptibilities. The parent strains used included ATCC 700057 and clinical isolates from the restriction endonuclease analysis (REA) groups BI and K. Serial passage experiments were also performed with vancomycin-resistant and vancomycin-susceptible Enterococcus faecium and Enterococcus faecalis. The goal of this study is to identify mutations associated with reduced surotomycin susceptibility in C. difficile and enterococci. Illumina sequence data generated for the parent strains and serial passage isolates were compared. We identified nonsynonymous mutations in genes coding for cardiolipin synthase in C. difficile ATCC 700057, enoyl-(acyl carrier protein) reductase II (FabK) and cell division protein FtsH2 in C. difficile REA type BI, and a PadR family transcriptional regulator in C. difficile REA type K. Among the 4 enterococcal strain pairs, 20 mutations were identified, and those mutations overlap those associated with daptomycin resistance. These data give insight into the mechanism of action of surotomycin against C. difficile, possible mechanisms for resistance emergence during clinical use, and the potential impacts of surotomycin therapy on intestinal enterococci. C lostridium difficile is a Gram-positive anaerobic spore-forming bacterium and a causative agent of health care-associated infections (HAIs). C. difficile infection (CDI; alternatively called C. difficile-associated diarrhea) can occur after disruption of the normal microbiota of the gastrointestinal (GI) tract, thereby decreasing colonization resistance and allowing for C. difficile outgrowth (1). Toxin production by C. difficile can lead to severe disease. Over the last two decades, the incidence of CDI has increased dramatically, especially among elderly health care patients (1-3). A recent Centers for Disease Control and Prevention report on antibiotic resistance threats in the United States classifies C. difficile as an urgent public health threat, as it causes an estimated 250,000 infections per year, leading to an estimated 14,000 deaths and at least $1 billion in medical costs (2).CDI can be treated with antibiotics, but recurrence can occur after a successful therapy and is a persistent concern (3). Vancomycin, metronidazole, and the recently FDA-approved drug fidaxomicin are used to treat CDI (1, 3, 4). Surotomycin (CB-183,315) is a cyclic lipopeptide antibiotic and daptomycin analogue that...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Adams

Mascio

et al. 2015

Antimicrob Agents Chemother

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“…33 Notably, cardiolipin is known to be a significant negatively charged polar glycerophospholipid component of the C. difficile cell plasma membrane. 34 In this work, we investigated the use of mitochondriotropic, cationic cyclohexyl-DQA bolasomes, with alkyl chain lengths of 10 and 12, as an ASO delivery strategy for C. difficile. The anionic ASO chosen to form complexes with cationic bolasomes for this study were chimeric 2′-Omethyl flanked phosphorothioate ASO gapmers.…”

mentioning

confidence: 99%

Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for <em>Clostridium difficile</em>

Hegarty

Krzeminski

Sharma

et al. 2016

IJN

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Despite being a conceptually appealing alternative to conventional antibiotics, a major challenge toward the successful implementation of antisense treatments for bacterial infections is the development of efficient oligonucleotide delivery systems. Cationic vesicles (bolasomes) composed of dequalinium chloride (“DQAsomes”) have been used to deliver plasmid DNA across the cardiolipin-rich inner membrane of mitochondria. As cardiolipin is also a component of many bacterial membranes, we investigated the application of cationic bolasomes to bacteria as an oligonucleotide delivery system. Antisense sequences designed in silico to target the expression of essential genes of the bacterial pathogen, Clostridium difficile , were synthesized as 2′- O -methyl phosphorothioate gapmer antisense oligonucleotides (ASO). These antisense gapmers were quantitatively assessed for their ability to block mRNA translation using luciferase reporter and C. difficile protein expression plasmid constructs in a coupled transcription–translation system. Cationic bolaamphiphile compounds (dequalinium derivatives) of varying alkyl chain length were synthesized and bolasomes were prepared via probe sonication of an aqueous suspension. Bolasomes were characterized by particle size distribution, zeta potential, and binding capacities for anionic oligonucleotide. Bolasomes and antisense gapmers were combined to form antisense nanocomplexes. Anaerobic C. difficile log phase cultures were treated with serial doses of gapmer nanocomplexes or equivalent amounts of empty bolasomes for 24 hours. Antisense gapmers for four gene targets achieved nanomolar minimum inhibitory concentrations for C. difficile , with the lowest values observed for oligonucleotides targeting polymerase genes rpoB and dnaE . No inhibition of bacterial growth was observed from treatments at matched dosages of scrambled gapmer nanocomplexes or plain, oligonucleotide-free bolasomes compared to untreated control cultures. We describe the novel application of cationic bolasomes to deliver ASOs into bacteria. We also report the first successful in vitro antisense treatment to inhibit the growth of C. difficile .

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The anaerobic biosynthesis of plasmalogens

Goldfine

2017

FEBS Letters

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The biosynthesis of plasmalogens in anaerobic bacteria differs fundamentally from that in animal cells. Firstly, the formation of the alk-1 0 -enyl ether bond in animal cells is oxygen dependent. Secondly, the first step in plasmalogen formation in animal cells is an acylation of dihydroxyacetone phosphate, which has been ruled out as a precursor in anaerobes. In bacteria the alk-1 0 -enyl ether bond is formed after the fully formed acyl glycerolipids are synthesized. Evidence will be presented for the conversion of the sn-1 acyl-linked chain to an O-alk-1 0 -enyl ether by an as yet unknown mechanism.

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Clostridium difficile contains plasmalogen species of phospholipids and glycolipids

Cited by 35 publications

References 21 publications

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Mutations Associated with Reduced Surotomycin Susceptibility in Clostridium difficile and Enterococcus Species

Bolaamphiphile-based nanocomplex delivery of phosphorothioate gapmer antisense oligonucleotides as a treatment for <em>Clostridium difficile</em>

The anaerobic biosynthesis of plasmalogens

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