Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium

Fernanda L. Paganelli, Tim van de Kamer, Ellen C. Brouwer, Helen L. Leavis, Neil Woodford, Marc J.M. Bonten, Rob J.L. Willems, Antoni P.A. Hendrickx*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Enterococcus faecium is a multidrug-resistant (MDR) nosocomial pathogen causing significant morbidity in debilitated patients. New antimicrobials are needed to treat antibiotic-resistant E. faecium infections in hospitalised patients. E. faecium incorporates lipoteichoic acid (LTA) (1,3-polyglycerol-phosphate linked to glycolipid) in its cell wall. The small-molecule inhibitor 1771 [2-oxo-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)ethyl 2-naphtho[2,1-b]furan-1-ylacetate] specifically blocks the activity of Staphylococcus aureus LtaS synthase, which polymerises 1,3-glycerolphosphate into LTA polymers. Here we characterised the effects of the small-molecule inhibitor 1771 on the growth of E. faecium isolates, alone (28 strains) or in combination with the antibiotics vancomycin, daptomycin, ampicillin, gentamicin or linezolid (15 strains), and on biofilm formation (16 strains). Inhibition of LTA synthesis at the surface of the cell by compound 1771 in combination with current antibiotic therapy abrogates enterococcal growth in vitro but does not affect mature E. faecium biofilms. Targeting LTA synthesis may provide new possibilities to treat MDR E. faecium infections.

Original languageEnglish
Pages (from-to)355-363
Number of pages9
JournalInternational Journal of Antimicrobial Agents
Volume49
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017

Bibliographical note

Funding Information:
Funding: RJLW has received funding from the European Union Seventh Framework Programme (FP7-HEALTH-2011-single-stage) under grant agreement no. 282004, EvoTAR.

Publisher Copyright:
© 2017 Elsevier B.V. and International Society of Chemotherapy

Keywords

  • Antibiotic resistance
  • Biofilms
  • Compound 1771
  • Enterococcus faecium
  • Lipoteichoic acid
  • LtaS

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