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A Tandem Liquid Chromatography–Mass Spectrometry-based Approach for Metabolite Analysis of Staphylococcus aureus
Published on: March 28, 2017
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A putative cro-like repressor contributes to arylomycin resistance in Staphylococcus aureus.
Arryn Craney1, Floyd E Romesberg2
1Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
Antimicrobial Agents and Chemotherapy
|March 11, 2015
Summary
New antibiotics called arylomycins target type I signal peptidase (SPase) in bacteria. Researchers found mutations in a specific gene help Staphylococcus aureus resist these drugs by altering cell wall synthesis.
Area of Science:
- Microbiology
- Drug Discovery
- Molecular Biology
Background:
- Antibiotic resistance is a major global health threat, driving the search for novel antibiotics.
- Arylomycins are a new class of antibiotics targeting type I signal peptidase (SPase), crucial for protein secretion.
- Limited arylomycin activity against Staphylococcus aureus necessitates understanding resistance mechanisms.
Purpose of the Study:
- Investigate the basis of limited arylomycin activity against Staphylococcus aureus.
- Characterize the transcriptional response of S. aureus to arylomycin M131.
- Identify genetic factors contributing to arylomycin resistance in S. aureus.
Main Methods:
- Assessed susceptibility of S. aureus strains to arylomycin derivatives.
- Examined the effect of tunicamycin cotreatment on arylomycin-resistant strains.
- Performed transcriptional profiling of S. aureus exposed to arylomycin M131.
- Selected for and analyzed spontaneous arylomycin-resistant mutants.
Main Results:
- Observed variable susceptibility of S. aureus to arylomycins; tunicamycin sensitized resistant strains.
- Arylomycin M131 induced upregulation of the cell wall stress stimulon and a specific operon in S. aureus.
- Mutations in a putative transcriptional regulator gene correlated with and conferred arylomycin resistance.
- In vitro selection confirmed mutations in this regulator are sufficient for resistance.
Conclusions:
- S. aureus employs specific genetic mechanisms to cope with SPase inhibition by arylomycins.
- A putative transcriptional regulator plays a key role in S. aureus resistance to arylomycin antibiotics.
- Understanding these resistance pathways is crucial for developing effective anti-staphylococcal therapies.
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