The antifungal caspofungin increases fluoroquinolone activity against Staphylococcus aureus biofilms by inhibiting N-acetylglucosamine transferase.
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.
Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
Wafi
W
Siala
Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KULeuven, 3000 Leuven, Belgium.|Department of Molecular Microbiology, VIB, KULeuven, 3000 Leuven, Belgium.
Soňa
S
Kucharíková
Department of Materials Engineering, KULeuven, 3000 Leuven, Belgium.
Annabel
0000-0002-4890-0177
A
Braem
Department of Materials Engineering, KULeuven, 3000 Leuven, Belgium.
Jef
J
Vleugels
Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
Paul M
0000-0002-7121-3623
PM
Tulkens
Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
Marie-Paule
MP
Mingeot-Leclercq
Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KULeuven, 3000 Leuven, Belgium.|Department of Molecular Microbiology, VIB, KULeuven, 3000 Leuven, Belgium.
Patrick
0000-0002-1542-897X
P
Van Dijck
Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
Françoise
F
Van Bambeke
D000117:Acetylglucosamine / Q000096:biosynthesis; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects*; D000077336:Caspofungin; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D055666:Lipopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology*
D000935:Antifungal Agents; D054714:Echinocandins; D024841:Fluoroquinolones; D055666:Lipopeptides; C113831:poly-N-acetyl glucosamine; D017351:N-Acetylglucosaminyltransferases; D000077336:Caspofungin; D000117:Acetylglucosamine