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


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Article Info

DATE

2022-05-30

AUTHORS

Momen Askoura, Nehal Yousef, Basem Mansour, Fatma Al-zahraa A. Yehia

ABSTRACT

BackgroundAntimicrobial 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.MethodsTerbinafine 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.ResultsTerbinafine 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.ConclusionsPresent findings strongly suggest that terbinafine could be used safely and efficiently as an anti-virulent agent to combat S. aureus infections. More... »

PAGES

21

References to SciGraph publications

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  • 2020-01-18. Attenuated total reflection: Fourier transform infrared spectroscopy for detection of heterogeneous vancomycin—intermediate Staphylococcus aureus in WORLD JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY
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    http://scigraph.springernature.com/pub.10.1186/s12941-022-00513-7

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    http://dx.doi.org/10.1186/s12941-022-00513-7

    DIMENSIONS

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    PUBMED

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    30 schema:description BackgroundAntimicrobial 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.MethodsTerbinafine 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.ResultsTerbinafine 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.ConclusionsPresent findings strongly suggest that terbinafine could be used safely and efficiently as an anti-virulent agent to combat S. aureus infections.
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    37 ConclusionsPresent findings
    38 CrtN
    39 Fourier transform
    40 H bonds
    41 S. aureus
    42 S. aureus biofilm formation
    43 S. aureus gene expression
    44 S. aureus infection
    45 S. aureus membranes
    46 S. aureus pathogenesis
    47 S. aureus virulence
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    49 SigB
    50 Staphylococcus aureus
    51 acid
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    58 amino acids
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    65 aureus
    66 aureus biofilm formation
    67 aureus infection
    68 aureus virulence
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    70 biofilm formation
    71 biosynthesis
    72 blood
    73 bonds
    74 broad spectrum
    75 cell autoaggregation
    76 cells
    77 changes
    78 checkerboard assay
    79 combat S. aureus infections
    80 combination
    81 conventional antibiotics
    82 counting
    83 crystal violet assay
    84 dermatophytosis
    85 desaturase
    86 docking
    87 effect
    88 effect of terbinafine
    89 energy
    90 exopolysaccharide production
    91 expression
    92 findings
    93 formation
    94 gene expression
    95 human blood
    96 hydrophilic interactions
    97 hydrophobicity
    98 icaA
    99 impact
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    102 influence
    103 inhibitory effect
    104 inhibitory potential
    105 inhibits
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    108 kcal/
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    135 terbinafine
    136 therapeutic options
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    140 untreated cells
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