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JAC Advance Access originally published online on March 22, 2009
Journal of Antimicrobial Chemotherapy 2009 63(6):1156-1162; doi:10.1093/jac/dkp094
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Original research

Disruption of D-alanyl esterification of Staphylococcus aureus cell wall teichoic acid by the β-lactam resistance modifier (–)-epicatechin gallate

Patricia Bernal, Mire Zloh and Peter W. Taylor*

School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK

Received 2 December 2008; returned 30 January 2009; revised 4 February 2009; accepted 24 February 2009

* Corresponding author. Tel/Fax: +44-20-753-5867; E-mail: peter.taylor{at}pharmacy.ac.uk

Objectives: The naturally occurring polyphenol (–)-epicatechin gallate (ECg) increases oxacillin susceptibility in mecA-containing strains of Staphylococcus aureus. Decreased susceptibility to lysostaphin suggests alterations to the wall teichoic acid (WTA) content of ECg-grown bacteria. Changes in WTA structure in response to ECg were determined.

Methods: Nuclear magnetic resonance spectroscopy of purified monomers from S. aureus was used to elucidate WTA structures. Molecular modelling of WTA chains was employed to determine their spatial configuration.

Results: ECg-grown methicillin-resistant S. aureus (MRSA) strains BB568 and EMRSA-16 displayed markedly reduced resistance to oxacillin, had thickened cell walls and separated poorly. Growth in ECg-supplemented medium reduced the substitution of the WTA backbone by D-alanine (D-Ala); ratios of N-acetyl glucosamine to D-Ala were reduced from 0.6 and 0.49 (for BB568 and EMRSA-16) to 0.3 and 0.28, respectively. Molecular simulations indicated a decrease in the positive charge of the bacterial wall, confirmed by increased binding of cationized ferritin, and an increase in WTA chain flexibility to a random coil conformation.

Conclusions: Structural elucidation and molecular modelling of WTA indicated that conformational changes associated with reduced D-Ala substitution may contribute to the increased susceptibility of MRSA to β-lactam antibiotics and account for other elements of the ECg-induced phenotype.

Keywords: epicatechin gallate , bacterial cell wall structure , β-lactam resistance , MRSA


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