Absolutely delighted to be able to share our paper describing the evolution of vancomycin resistance in C. difficile using evolution – out today in PLOS Biology journals.plos.org/plosbiology/... A THREAD (1/10) www.sheffield.ac.uk/news/scienti... - ThreadSky

robfagan.bsky.social • 206 days ago

Absolutely delighted to be able to share our paper describing the evolution of vancomycin resistance in C. difficile using evolution – out today in PLOS Biology
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002741

A THREAD (1/10)

https://www.sheffield.ac.uk/news/scientists-discover-superbugs-rapid-path-antibiotic-resistance

Comments

pssalgado.bsky.social•205 days ago

Great work, congratulations to all involved! And good to see it here in #microsky

dutchscientist.bsky.social•206 days ago

Congrats! Looks really interesting 🙂

lizscurious.bsky.social•201 days ago

Congrats, nice to see this out.

robfagan.bsky.social•206 days ago

We performed a large-scale evolution of 10 replicate populations of C. difficile under ramping vancomycin selection. We found resistance evolves rapidly in laboratory settings, with some isolates reaching 32x the initial MIC in only 250 generations!

(2/10)

robfagan.bsky.social•206 days ago

This resistance was however accompanied by fitness costs – all resistant strains had growth defects and several also had severe sporulation defects. Are these fitness effects a hindrance to the emergence of resistance in the clinic?

(3/10)

robfagan.bsky.social•206 days ago

We then sequenced both resistant isolates and populations over time, identifying 2 distinct pathways to resistance: one involving the vanG cluster, & the other involving an uncharacterised D,D-carboxypeptidase which we’ve named DacJ & a dedicated two-component system (DacRS)

(4/10)

robfagan.bsky.social•206 days ago

Next, we introduced individual dacS mutations, IDed in the evolution experiment, back into a clean genetic background. A single dacS SNP could lead to vancomycin resistance but did not fully recapitulate the phenotype of the evolved resistant strain

(5/10)

robfagan.bsky.social•206 days ago

dacS SNPs led to huge increases in transcription of dacRS and dacJ and depleted vancomycin binding sites in the cell wall

(6/10)

robfagan.bsky.social•206 days ago

But dacS clearly wasn’t the whole story. Resequencing with nanopore found a 30bp duplication in vanS that we’d missed in short-read sequencing. The vanS mutation leads to massive overexpression of the rest of the vanG cluster

(7/10)

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