Pharmacokinetics and Pharmacodynamics of Fungal Defensin NZX Against Staphylococcus aureus-Induced Mouse Peritonitis Model

Abstract

Staphylococcus aureus (S. aureus) is one of the most common pathogenic bacteria responsible for causing a life-threatening peritonitis disease. NZX, as a variant of fungal defensin plectasin, displayed potent antibacterial activity against S. aureus. In this study, the antibacterial and resistance characteristics, pharmacokinetics, and pharmacodynamics of NZX against the S. aureus E48 and S. aureus E48-induced mouse peritonitis model were studied, respectively. NZX exhibited a more rapid killing activity to S. aureus (minimal inhibitory concentration, 1 μg/ml) compared with linezolid, ampicillin and daptomycin, and serial passaging of S. aureus E48 for 30 days at 1/2 × MIC, NZX had a lower risk of resistance compared with ampicillin and daptomycin. Also, it displayed a high biocompatibility and tolerance to physiological salt, serum environment, and phagolysosome proteinase environment, except for acid environment in phagolysosome. The murine serum protein-binding rate of NZX was 89.25% measured by ultrafiltration method. Based on the free NZX concentration in serum after tail vein administration, the main pharmacokinetic parameters for T1/2, Cmax, Vd, MRT, and AUC ranged from 0.32 to 0.45 h, 2.85 to 20.55 μg/ml, 1469.10 to 2073.90 ml/kg, 0.32 to 0.56 h, and 1.11 to 8.89 μg.h/ml, respectively. Additionally, the in vivo pharmacodynamics against S. aureus demonstrated that NZX administrated two times by tail vein at 20 mg/kg could rescue all infected mice in the lethal mouse peritonitis model. And NZX treatment (20 mg/kg) significantly reduced CFU counts in the liver, lung, and spleen, especially for intracellular bacteria in the peritoneal fluid, which were similar or superior to those of daptomycin. In vivo efficacies of NZX against total bacteria and intracellular bacteria were significantly correlated with three PK/PD indices of ƒAUC/MIC, ƒCmax/MIC, and ƒT% > MIC analyzed by a sigmoid maximum-effect model. These results showed that NZX may be a potential candidate for treating peritonitis disease caused by intracellular S. aureus.

Polylactic Glycolic Acid-Mediated Delivery of Plectasin Derivative NZ2114 in Staphylococcus epidermidis Biofilms

“…A calibration curve was established under the experimental conditions ( n = 3), and the calibration curves showed a linear range of 8–512 μg/mL with correlation coefficients of R 2 greater than 0.999. The drug concentration in the samples was calculated [ 51 , 52 ].…”

“…The MIC values of NZ2114 nanoparticles were assessed using the broth microdilution method [ 52 ]. Briefly, S. epidermidis in the logarithmic growth phase (1 × 10 5 CFU/mL) was incubated with different concentrations of samples for 16 to 20 h at 37 °C.…”

Thinking on the Construction of Antimicrobial Peptide Databases: Powerful Tools for the Molecular Design and Screening

“…They are all involved in antimicrobial and immune regulation at trace levels and respond in vivo [ 14 , 15 , 18 , 20 , 21 , 22 , 23 ]. In addition, AMPs are also reported to have anticancer, antiviral, antiparasitic, and antibiofilm functions [ 24 , 25 , 26 ]. For example, Maximin-1, Dermaseptin-B2, Macropin-1, HBD-3, and Opis were discovered in 2002, 2010, 2012, 2017, and 2020, respectively, and have antiviral, antimicrobial, antifungal, and antiparasitic properties [ 18 , 20 , 23 , 25 ].…”

“…For example, Maximin-1, Dermaseptin-B2, Macropin-1, HBD-3, and Opis were discovered in 2002, 2010, 2012, 2017, and 2020, respectively, and have antiviral, antimicrobial, antifungal, and antiparasitic properties [ 18 , 20 , 23 , 25 ]. On a basis of works over the past two decades, the “iron triangle” theory for the prevention and treatment of human and animal diseases has been recently proposed serving the One Health concept, consisting of AMPs, antibiotics, and vaccines and focusing on strong penetration, high internalization, and low AMR [ 26 , 27 , 28 , 29 , 30 , 31 ]. Most studies have emphasized that a better understanding of the structure and activity of peptides is vital and have demonstrated the value of databases to classify them.…”

“…Most AMPs suffer serious limitations with regard to low yield, instability, and toxicity. Therefore, it is necessary to establish an AMP database and to combine it with computer algorithms to efficiently and accurately predict and design new AMPs [ 52 , 53 ] and to further validate the iron triangle theory [ 26 , 27 , 28 , 29 , 30 , 31 ] and its application in health maintenance.…”