Antibiofilm and staphyloxanthin inhibitory potential of terbinafine against Staphylococcus aureus: in vitro and in vivo studies

Abstract

Background Antimicrobial resistance is growing substantially, which necessitates the search for novel therapeutic options. Terbinafine, an allylamine antifungal agent that exhibits a broad spectrum of activity and is used in the treatment of dermatophytosis, could be a possible option to disarm S. aureus virulence. Methods Terbinafine inhibitory effect on staphyloxanthin was characterized by quantitative measurement of staphyloxanthin intermediates and molecular docking. The effect of terbinafine on S. aureus stress survival was characterized by viable counting. The anti-biofilm activity of terbinafine on S. aureus was assessed by the crystal violet assay and microscopy. Changes in S. aureus membrane following treatment with terbinafine were determined using Fourier transform infrared (FTIR) analysis. The synergistic action of terbinafine in combination with conventional antibiotics was characterized using the checkerboard assay. qRT-PCR was used to evaluate the impact of terbinafine on S. aureus gene expression. The influence of terbinafine on S. aureus pathogenesis was investigated in mice infection model. Results Terbinafine inhibits staphyloxanthin biosynthesis through targeting dehydrosqualene desaturase (CrtN). Docking analysis of terbinafine against the predicted active site of CrtN reveals a binding energy of − 9.579 kcal/mol exemplified by the formation of H-bonds, H-arene bonds, and hydrophobic/hydrophilic interactions with the conserved amino acids of the receptor pocket. Terbinafine treated S. aureus was more susceptible to both oxidative and acid stress as well as human blood killing as compared to untreated cells. Targeting staphyloxanthin by terbinafine rendered S. aureus more sensitive to membrane acting antibiotics. Terbinafine interfered with S. aureus biofilm formation through targeting cell autoaggregation, hydrophobicity, and exopolysaccharide production. Moreover, terbinafine demonstrated a synergistic interaction against S. aureus when combined with conventional antibiotics. Importantly, terbinafine attenuated S. aureus pathogenesis using mice infection model. qRT-PCR revealed that terbinafine repressed expression of the transcriptional regulators sigB, sarA, and msaB, as well as icaA in S. aureus. Conclusions Present findings strongly suggest that terbinafine could be used safely and efficiently as an anti-virulent agent to combat S. aureus infections.

Riboflavin-Vancomycin Conjugate Enables Simultaneous Antibiotic Photo-Release and Photodynamic Killing against Resistant Gram-Positive Pathogens

“…In particular, S. aureus has a variety of defense mechanisms which are upregulated following oxidative burst, such as antioxidant enzymes and small molecules . We evaluated VanB2 against a panel of S.…”

“… 45 In particular, S. aureus has a variety of defense mechanisms which are upregulated following oxidative burst, such as antioxidant enzymes and small molecules. 46 We evaluated VanB2 against a panel of S. aureus strains (including methicillin resistant strain MRSA USA300), which exhibited a range of staphyloxanthin pigmentation. Staphyloxanthin is a membrane-bound antioxidant carotenoid responsible for the yellow-orange appearance of many S. aureus strains.…”

A novel volatile staphyloxanthin biosynthesis inhibitor

“…Both bacterial pallet and staphyloxanthin were subjected to FTIR analysis with a spectral scan (4000-400 cm -1 ) using FTIR spectrometer (NICOLET, USA) [28].…”

Quality assurance of postharvest grapes against Botrytis cinerea by terbinafine

“…Previous researches indicated that terbinafine can inhibit Penicillium spp., Trichoderma spp., Acremonium spp., and Staphylococcus spp. [ 12 , 13 ] Therefore, based on the safety and broad-spectrum antifungal properties of terbinafine, it may have potential to be developed as an agricultural fungicide.

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