β-lactamase inhibitory potential of kalafungin from marine Streptomyces in Staphylococcus aureus infected zebrafish

beta-lactamase inhibitors are potent synergistic drugs to deteriorate the multidrug-resistant bacteria. Here, we report the beta-lactamase inhibitory ability of kalafungin isolated from a marine sponge derived Streptomyces sp. SBRK1. The IC50 value of the kalafungin was calculated as 225.37 +/- 1.95 mu M against beta-lactamase. The enzyme kinetic analysis showed the Km value of 3.448 +/- 0.7 mu M and V-max value of 215.356 +/- 8 mu M/min and the inhibition mechanism was identified as uncompetitive type. Along with the antibacterial activity, the cell surface analysis of kalafungin treated Staphylococcus aureus cells revealed destruction of cell membrane in response to beta-lactamase inhibition. Molecular docking studies have confirmed the binding property of kalafungin against beta-lactamase with two hydrogen bonds. In vivo efficacy studies in the zebrafish model by green fluorescent protein expressing S. aureus infection, survival, safety and behavioral profile were reported. The toxicity and anti infection revealed that the compound was evidently active and safe to all organs. In conclusion, this is the first report on kalafungin with beta-lactamase inhibition and suggests that kalafungin may useful for synergic antibacterial therapy with beta-lactam drugs to overcome beta-lactamase-based resistance of any bacterial pathogens.

Automated summary

Kalafungin has potent inhibitory effects on beta-lactamase, leading to cell membrane destruction in Staphylococcus aureus. In vivo studies in zebrafish model demonstrated its effectiveness and safety, suggesting its potential for synergistic antibacterial therapy.