Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin

Jarosław Ruczyński,Piotr Rekowski,Izabela Rusiecka,Krzysztof Waleron,Iwona Gągało,Agnieszka Kozłowska,Ivan Kocić,Magdalena Alenowicz,Anna Kawiak,Katarzyna Turecka

doi:10.1038/s41598-019-40103-w

Abstract

In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. The antibacterial activity of the conjugates was tested on selected clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus sp. It turned out that all of them had superior antimicrobial activity in comparison to that of free Van, which became visible particularly against clinical MRSA strains. Furthermore, one of the conjugates was tested against MRSA - infected human cells. With respect to them, this compound showed high bactericidal activity. Next, the same conjugate was screened for its capacity to cross the blood brain barrier (BBB). Therefore, qualitative and quantitative analyses of the conjugate’s presence in the mouse brain slices were carried out after its iv administration. They indicated the conjugate’s presence in the brain in amount >200 times bigger than that of Van. The conjugates were safe with respect to erythrocyte toxicity (erythrocyte lysis assay). Van in the form of a conjugate with TP10 acquires superior pharmacodynamic and pharmacokinetic.

Highlights

In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain
Van is often used to treat life-threatening infections induced by multidrug resistant (MDR) bacteria such as S. aureus, Enterococcus spp. and C. difficile
All methicillin-resistant Staphylococcus aureus (MRSA) strains tested in this study indicated intermediate susceptibility to Van treatment

Summary

Introduction

Transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. Van is often used to treat life-threatening infections induced by multidrug resistant (MDR) bacteria such as S. aureus, Enterococcus spp. and C. difficile At present, these microorganisms are a leading cause of community-acquired infections that result in high morbidity and death rates. Of great concern, is the emergence of resistance among methicillin-resistant Staphylococcus aureus (MRSA) and enterococcal strains This phenomenon is due to the modification of Van’s binding target (replacement of C-terminal D-Ala residue by D-lactate or D-serine) which indicates low affinity to the antibiotic. A much higher prevalence concerns h-VISA (heterogenous vancomycin intermediate S. aureus) or VISA which poses a significant threat because these bacteria produce persistent infection requiring hospitalization, prolonged vancomycin medication with a considerable risk of treatment failure[3] Another important limitation of Van results from its chemical features. Successful approaches in this field have focused on among others:

Methods

Results

Conclusion