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Pyochelin methylation by S. aureus transposon library mutants

ABSTRACT: Manuscript Title: Pyochelin biotransformation shapes bacterial competition. LC-MS/MS analysis of pyochelin methylation by S. aureus transposon library mutants.

INSTRUMENT(S): impact HD

ORGANISM(S): Staphylococcus Aureus Lac (ncbitaxon:867914) Pseudomonas Aeruginosa Pao1 (ncbitaxon:208964)

SUBMITTER: Christian Jenul

PROVIDER: MSV000089233 | MassIVE | Sun Apr 10 22:03:00 BST 2022

REPOSITORIES: MassIVE

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Project description:Staphylococcus aureus thymidine-dependent small-colony variants (TD-SCVs) are frequently isolated from patients with chronic S. aureus infections after long-term treatment with trimethoprim-sulfamethoxazole (TMP-SMX). In TD-SCVs, mutations of thymidylate synthase (thyA, TS), essential for DNA synthesis, occur. However, it has never been shown, that TMP-SMX is responsible for the induction and selection of TD-SCVs. Short-term exposure of TMP-SMX induced the TD-SCV phenotype morphologically as shown in transmission electron-microscopy and on the transcriptional level by qRT-PCR in wild-type S. aureus, while selection of TD-SCVs with thyA mutations occurred only rarely after long-term exposure. In reversion experiments with clinical TD-SCVs, all revertants revealed compensating mutations at the initially identified mutation site. Whole DNA microarray analysis of a thyA deletion mutant (∆thyA), which exhibited the typical TD-SCV phenotype, identified tremendous alterations compared to the wild-type. Important virulence regulators such as agr, arlRS, sarA and major virulence determinants including hla, hlb, sspA, sspB and geh were down-regulated, while genes associated with the colonization capacity like fnbA, fnbB, spa, clfB, sdrC and sdrD were up-regulated. The expression of genes involved in pyrimidine and purine metabolism as well as in nucleotide interconversion changed significantly. The ∆thyA-mutant was attenuated in virulence in both, a Caenorhabditis elegans killing model and an acute murine pneumonia model. Furthermore, competition experiments in vitro and in vivo (using a chronic pneumonia mouse model) revealed a survival and growth advantage of the ∆thyA-mutant under low thymidine conditions and TMP-SMX exposure. In conclusion, our results clearly show for the first time that TMP-SMX induces the TD-SCV phenotype after short-term exposure in S. aureus and that long-term exposure selects thyA mutations providing an advantage for TD-SCVs under specified conditions. Thus, our results help to understand the dynamic processes of induction and selection of S. aureus TD-SCVs during TMP-SMX exposure.

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Pyochelin methylation by S. aureus transposon library mutants

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