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Published on: January 3, 2020
Genetic Adaptation of a Mevalonate Pathway Deficient Mutant in Staphylococcus aureus
Sebastian Reichert1, Patrick Ebner1, Eve-Julie Bonetti2
1Microbial Genetics, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany.
Abstract:
In this study we addressed the question how a mevalonate (MVA)-auxotrophic Staphylococcus aureusΔmvaS mutant can revert to prototrophy. This mutant couldn't grow in the absence of MVA. However, after a long lag-phase of 4-6 days the mutant adapted from auxotrophic to prototrophic phenotype. During that time, it acquired two point mutations: One mutation in the coding region of the regulator gene spx, which resulted in an amino acid exchange that decreased Spx function. The other mutation in the upstream-element within the core-promoter of the mevalonolactone lactonase gene drp35. This mutation led to an increased expression of drp35. In repeated experiments the mutations always occurred in spx and drp35 and in the same order. The first detectable mutation appeared in spx and allowed slight growth; the second mutation, in drp35, increased growth further. Phenotypical characterizations of the mutant showed that small amounts of the lipid-carrier undecaprenol are synthesized, despite the lack of mvaS. The growth of the adapted clone, ΔmvaSad, indicates that the mutations reawake a rescue bypass. We think that this bypass enters the MVA pathway at the stage of MVA, because blocking the pathway downstream of MVA led to growth arrest of the mutant. In addition, the lactonase Drp35 is able to convert mevalonolactone to MVA. Summarized, we describe here a mutation-based two-step adaptation process that allows resuscitation of growth of the ΔmvaS mutant.
Insights
Staphylococcus aureus lacking MVA synthesis can regain growth through two mutations. These genetic changes in spx and drp35 reactivate a mevalonate pathway bypass, enabling prototrophy.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Mevalonate (MVA) is essential for Staphylococcus aureus growth.
- A ΔmvaS mutant is auxotrophic, requiring MVA for survival.
- This study investigates the adaptation mechanism of the auxotrophic mutant.
Purpose of the Study:
- To elucidate the genetic and molecular basis of how a mevalonate-auxotrophic Staphylococcus aureus mutant reverts to prototrophy.
- To identify the specific mutations and pathways involved in this adaptation process.
Main Methods:
- Generating and culturing a mevalonate-auxotrophic Staphylococcus aureus ΔmvaS mutant.
- Phenotypic characterization of mutant growth under different conditions.
- Genetic analysis to identify acquired mutations (sequencing of spx and drp35 genes).
- Enzymatic assays to confirm Drp35 activity.
Main Results:
- The ΔmvaS mutant adapted to prototrophy after a 4-6 day lag phase.
- Two sequential point mutations were identified: one in the regulator gene spx (decreasing Spx function) and another in the drp35 promoter (increasing drp35 expression).
- The adapted mutant (ΔmvaSad) synthesized undecaprenol and showed restored growth, indicating a reactivated MVA pathway bypass.
- Drp35 was confirmed to convert mevalonolactone to MVA.
Conclusions:
- A two-step mutation process enables Staphylococcus aureus ΔmvaS to regain MVA prototrophy.
- The mutations in spx and drp35 cooperate to establish a functional bypass of the MVA pathway.
- This adaptation highlights the genetic plasticity of S. aureus in response to metabolic stress.
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