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| Status |
Public on Dec 10, 2022 |
| Title |
HexSDF are Required for Synthesis of a Novel Glycolipid that Mediates Daptomycin and Bacitracin Resistance in C. difficile |
| Organism |
Clostridioides difficile |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Clostridioides difficile is a Gram-positive opportunistic pathogen that results in 250,000 infections, 12,000 deaths, and $1 billion in medical costs in the US each year. There has been recent interest in using a daptomycin analog, Surotomycin, to treat C. difficile infections. Daptomycin interacts with both phosphatidylglycerol and Lipid II to disrupt the membrane and halt peptidoglycan synthesis. C. difficile has an unusual lipid membrane composition as it has no phosphatidylserine or phosphatidylethanolamine, and ~50% of its membrane is composed of glycolipids, including the unique C. difficile lipid aminohexosyl-hexosyldiradylglycerol (HNHDRG). We identified a two-component system (TCS) HexRK that is required for C. difficile resistance to daptomycin. Using RNAseq we found that HexRK regulates a three gene operon of unknown function hexSDF. Based on bioinformatic predictions, hexS encodes a monogalactosyldiacylglycerol synthase, hexD encodes a polysaccharide deacetylase, and hexF encodes an MprF-like flippase. We find that deletion of hexRK leads to a 4-fold decrease in daptomycin MIC, and that deletion of hexSDF leads to an 8-16-fold decrease in daptomycin MIC. The ∆hexSDF mutant is also 4-fold less resistant to bacitracin but no other cell wall active antibiotics. Our data indicate that in the absence of HexSDF the phospholipid membrane composition is altered. In WT C. difficile the unique glycolipid, HNHDRG makes up ~17% of the lipids in the membrane. However, in a ∆hexSDF mutant, HNHDRG is completely absent. While it is unclear how HNHDRG contributes daptomycin resistance, the requirement for bacitracin resistance suggests it has a general role in cell membrane biogenesis.
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| Overall design |
RNA-seq comparision of WT R20291 vs ∆hexRK
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| Contributor(s) |
Pannullo AG, Guan Z, Goldfine H, Ellermeier CD |
| Citation(s) |
36786594 |
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| Submission date |
Dec 05, 2022 |
| Last update date |
May 12, 2023 |
| Contact name |
Anthony Pannullo |
| E-mail(s) |
anthony-pannullo@uiowa.edu
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| Organization name |
University of Iowa
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| Street address |
431 Newton Road
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| City |
Iowa City |
| State/province |
IA |
| ZIP/Postal code |
52242 |
| Country |
USA |
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| Platforms (1) |
| GPL32868 |
NextSeq 2000 (Clostridioides difficile) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA908828 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE220119_WT_delta_hexRK_DESeq2.txt.gz |
143.0 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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