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Cited by 289

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 access
Campbell, Jennifer, Singh, Atul K., Santa Maria, John P., Kim, Younghoon, Brown, Stephanie, Swoboda, Jonathan G., Mylonakis, Eleftherios, Wilkinson, Brian J., Walker, Suzanne·2011·ACS Chemical Biology
DOI 10.1021/cb100269f
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Abstract

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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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
DOI
10.1021/cb100269f
OpenAlex
W2013798053
Cited by
289
References
43
FWCI
8.84
Type
journal article
Language
en
Open access
green

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