1. Nat Commun. 2016 Nov 3;7:13286. doi: 10.1038/ncomms13286.

The antifungal caspofungin increases fluoroquinolone activity against
Staphylococcus aureus biofilms by inhibiting N-acetylglucosamine transferase.

Siala W(1), Kucharíková S(2,)(3), Braem A(4), Vleugels J(4), Tulkens PM(1),
Mingeot-Leclercq MP(1), Van Dijck P(2,)(3), Van Bambeke F(1).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, 1200 Brussels, Belgium. (2)Laboratory of
Molecular Cell Biology, Institute of Botany and Microbiology, KULeuven, 3000
Leuven, Belgium. (3)Department of Molecular Microbiology, VIB, KULeuven, 3000
Leuven, Belgium. (4)Department of Materials Engineering, KULeuven, 3000 Leuven,

Biofilms play a major role in Staphylococcus aureus pathogenicity but respond
poorly to antibiotics. Here, we show that the antifungal caspofungin improves the
activity of fluoroquinolones (moxifloxacin, delafloxacin) against S. aureus
biofilms grown in vitro (96-well plates or catheters) and in vivo (murine model
of implanted catheters). The degree of synergy among different clinical isolates 
is inversely proportional to the expression level of ica operon, the products of 
which synthesize poly-N-acetyl-glucosamine polymers, a major constituent of
biofilm matrix. In vitro, caspofungin inhibits the activity of IcaA, which shares
homology with β-1-3-glucan synthase (caspofungin's pharmacological target in
fungi). This inhibition destructures the matrix, reduces the concentration and
polymerization of exopolysaccharides in biofilms, and increases fluoroquinolone
penetration inside biofilms. Our study identifies a bacterial target for
caspofungin and indicates that IcaA inhibitors could potentially be useful in the
treatment of biofilm-related infections.

DOI: 10.1038/ncomms13286 
PMID: 27808087  [PubMed - in process]