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.

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

“…[246] Halogenated phenazine (HP) analogue 14, inspired by marine antibiotic 2-bromo-1-hydroxyphenezine, is able to efficiently eradicate biofilms formed by MRSA, methicillinresistant S. epiderimdis (MRSE), and VRE with minimum biofilm eradication concentrations (MBECs) of 12.5 mm, 1.56 mm,a nd 0.20 mm,r espectively.T his excellent potencyi s promising for future development. [252] Several other excellent strategies based on synthetic and natural product derived compounds have been reported, including antimicrobial bridged bicyclicpeptides [253] and promysalin. [247] Cationic amphiphiles such as quaternary ammonium amphiphiles [248] have also shown antibiofilm activity.R ecently,c ationic pillararenes ( Figure 17) were revealed to inhibit biofilm formation effectively at sub-MIC concentrations in several clinically important Gram-positive pathogens including S. aureus and E. faecalis.…”

“…As ac onsequence,t he S. aureus biofilm matrix structure becomes vulnerable to fluoroquinolone treatment both in vitro and in vivo at clinically relevant doses. [252] Several other excellent strategies based on synthetic and natural product derived compounds have been reported, including antimicrobial bridged bicyclicpeptides [253] and promysalin. [254]…”

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

“…[247] Es ist bereits bekannt, dass kationische Amphiphile,w ie quartäre Ammonium-Amphiphile, [248] Antibiofilm-Aktivitäta ufzeigen. [252] Einige andere außergewçhnliche Strategien, die auf synthetischen und naturstoffähnlichen Verbindungen basieren, wurden bereits verçffentlicht, so zum Beispiel antimikrobiell wirksame verbrückte bizyklische Peptide [253] und der Wirkstoff Promysalin. Darüber hinaus sind diese Verbindungen nicht toxisch fürh umane Zellen.…”

“…Daraus resultiert eine erhçhte Anfälligkeit der S.-aureus-Biofilm-Matrixstruktur gegenüber Fluorchinolonen, sowohl in vitro als auch in vivo, in klinisch relevanter Dosierung. [252] Einige andere außergewçhnliche Strategien, die auf synthetischen und naturstoffähnlichen Verbindungen basieren, wurden bereits verçffentlicht, so zum Beispiel antimikrobiell wirksame verbrückte bizyklische Peptide [253] und der Wirkstoff Promysalin. [254]…”

Antifungal Caspofungin Sensitizes MRSA Isolates Towards Zabofloxacin, a Proteomic Study

“…The approach of screening and repurposing of molecules of completely disparate clinical indications has seized renovated interest, as reported by a number of latest studies 8 . Among the suggested drugs used in combination with other antibiotics for the eradication of MRSA infections are: the antirheumatic auranofin, the organoselenium compound ebselen, the anthelmintic ivermectin, and anticancer agents clomiphene and 5-fluoro-2'-deoxyuridine 9,10 . The repurposing strategy was applied as well to hinder the bacterial virulence instead of bacterial viability, where naftifine, an antifungal agent, was stated to suppress staphyloxanthin biosynthesis, an essential virulence determinant of S. aureus responsible for its protection from the host oxidant killing activity 9 .…”