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

Abstract

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.

• Authors: Wafi Siala, Soňa Kucharíková, Annabel Braem, Jef Vleugels, Paul M Tulkens, Marie-Paule Mingeot-Leclercq, Patrick Van Dijck, Françoise Van Bambeke
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 13286 (11 03 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27808087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Echinocandins
• Fluoroquinolones
• Lipopeptides
• poly-N-acetyl glucosamine
• N-Acetylglucosaminyltransferases
• Caspofungin
• Acetylglucosamine

Topics

• Acetylglucosamine (biosynthesis)
• Animals
• Antifungal Agents (pharmacology, therapeutic use)
• Biofilms (drug effects)
• Caspofungin
• Disease Models, Animal
• Drug Resistance, Bacterial (genetics)
• Drug Synergism
• Echinocandins (pharmacology, therapeutic use)
• Female
• Fluoroquinolones (pharmacology, therapeutic use)
• Humans
• Lipopeptides (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• N-Acetylglucosaminyltransferases (antagonists & inhibitors, metabolism)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects, physiology)