title: Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium.
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.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Fernanda L
authors.initials: FL
authors.lastname: Paganelli
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: van de Kamer
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Brouwer
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Leavis
authors.affiliation: Antimicrobial Resistance and Healthcare Associated Infections Reference Unit (AMRHAI), National Infection Service, Public Health England, London, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Woodford
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc J M
authors.initials: MJ
authors.lastname: Bonten
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rob J L
authors.initials: RJ
authors.lastname: Willems
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: a.p.a.hendrickx-4@umcutrecht.nl.
authors.forename: Antoni P A
authors.initials: AP
authors.lastname: Hendrickx
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D016984:Enterococcus faecium / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D008826:Microbial Sensitivity Tests; D013682:Teichoic Acids / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D013682:Teichoic Acids; C009900:lipoteichoic acid
keywords: Antibiotic resistance; Biofilms; Compound 1771; Enterococcus faecium; Lipoteichoic acid; LtaS