The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index.
Synthetic Lethal Compound Combinations Reveal a Fundamental Connection between Wall Teichoic Acid and Peptidoglycan Biosyntheses in Staphylococcus aureus
Open accessAbstract
Methicillin resistance in Staphylococcus aureus depends on the production of mecA, which encodes penicillin-binding protein 2A (PBP2A), an acquired peptidoglycan transpeptidase (TP) with reduced susceptibility to β-lactam antibiotics. PBP2A cross-links nascent peptidoglycan when the native TPs are inhibited by β-lactams. Although mecA expression is essential for β-lactam resistance, it is not sufficient. Here we show that blocking the expression of wall teichoic acids (WTAs) by inhibiting the first enzyme in the pathway, TarO, sensitizes methicillin-resistant S. aureus (MRSA) strains to β-lactams even though the β-lactam-resistant transpeptidase, PBP2A, is still expressed. The dramatic synergy between TarO inhibitors and β-lactams is noteworthy not simply because strategies to overcome MRSA are desperately needed but because neither TarO nor the activities of the native TPs are essential in MRSA strains. The "synthetic lethality" of inhibiting TarO and the native TPs suggests a functional connection between ongoing WTA expression and peptidoglycan assembly in S. aureus. Indeed, transmission electron microscopy shows that S. aureus cells blocked in WTA synthesis have extensive defects in septation and cell separation, indicating dysregulated cell wall assembly and degradation. Our studies imply that WTAs play a fundamental role in S. aureus cell division and raise the possibility that synthetic lethal compound combinations may have therapeutic utility for overcoming antibiotic-resistant bacterial infections.
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Cites
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“Invasive beta-lactamresistant S. aureus (methicillin-resistant SA, or MRSA) infections are directly responsible for 20,000 deaths annually in the United States (2).”
BackgroundInfluentialLinezolid resistance in a clinical isolate of Staphylococcus aureus
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Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions
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Antibiotics: Actions, Origins, Resistance
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Weidenmaier, C., Kokai-Kun, J. F., Kristian, S. A., Chanturiya, T., Kalbacher, H., Gross, M., Nicholson, G., Neumeister, B., Mond, J. J., & Peschel, A. (2004) · Nature Medicine · doi:10.1038/nm991 · Cited by 560
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Wall Teichoic Acid Function, Biosynthesis, and Inhibition
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Cited by
Wall Teichoic Acids of Gram-Positive Bacteria
Brown, S., Santa Maria, J. P., & Walker, S. (2013) · Annual Review of Microbiology · doi:10.1146/annurev-micro-092412-155620 · Cited by 966
Self-citationCombination approaches to combat multidrug-resistant bacteria
Worthington, R. J., & Melander, C. (2013) · Trends in Biotechnology · doi:10.1016/j.tibtech.2012.12.006 · Cited by 625
Antibiotic Resistance and the MRSA Problem
Vestergaard, M., Frees, D., & Ingmer, H. (2019) · Microbiology Spectrum · doi:10.1128/microbiolspec.gpp3-0057-2018 · Cited by 490
Bacterial Glycobiology: Rhamnose-Containing Cell Wall Polysaccharides in Gram-Positive Bacteria
Mistou, M.-Y., Sutcliffe, I. C., & van Sorge, N. M. (2016) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuw006 · Cited by 215
Naik, G. A. R. R., Roy, A. A., Mutalik, S., & Dhas, N. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.134977 · Cited by 47
RgpF Is Required for Maintenance of Stress Tolerance and Virulence in Streptococcus mutans
Kovacs, C. J., Faustoferri, R. C., & Quivey, R. G. (2017) · Journal of Bacteriology · doi:10.1128/jb.00497-17 · Cited by 28
SmdA is a Novel Cell Morphology Determinant in Staphylococcus aureus
(2022) · doi:10.1128/mbio.03404-21 · Cited by 18
Metadata
- Authors
- Campbell, J., Singh, A. K., Santa Maria, J. P., Kim, Y., Brown, S., Swoboda, J. G., Mylonakis, E., Wilkinson, B. J., & Walker, S.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-11-04
- Volume
- 6
- Issue
- 1
- Pages
- 106-116
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2013798053
- Cited by
- 289
- References
- 43
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- green
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