Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin

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.

Targeting Hidden Pathogens: Cell-Penetrating Enzybiotics Eradicate Intracellular Drug-Resistant Staphylococcus aureus

“…This may in part explain the difficulty to treat such infections with conventional antibiotics, which is in line with the observed ineffectiveness of the flucloxacillin treatment used as a control in our animal study. Towards this end, direct fusion of a CPP to the drug vancomycin has been shown to lead to increased intracellular killing in vitro and improved pharmacokinetics in vivo (57). Furthermore, a cleavable antibody-antibiotic conjugate has been developed for directed targeting of intracellular S. aureus (58).…”

Cell-Penetrating Peptides Derived from Animal Venoms and Toxins

“…Notably, vancomycin covalently linked to transportan 10 at is C-terminal, as in the conjugates AGYLLGK7(C(O)-Tra(1,4)-PEG4-C(O)-Van)INLKALAALAKKIL-amide and AGYLLGKINLKALAALAKKIL-Ala(Tra(1,4)-PEG4-C(O)-Van)-amide (where PEG4 is the linker group and Van is vancomycin), substantially increased the antibacterial activity of the conjugates against intracellular or extracellular compartmentalized multi-drug resistant bacteria in vitro. Moreover, transportan-vancomycin conjugates, including [Lys7(PEG4-Van)]TP10 and its fluorescent analog, translocated across the blood-brain barrier and accumulated in the cerebral tissue in an in vivo mouse model [ 77 ].…”

Enhancing Aqueous Solubility and Antibacterial Activity of Curcumin by Complexing with Cell-Penetrating Octaarginine

“… 17 , 18 Based on different physicochemical properties, there are many types of CPPs; however, amongst them, arginine-rich CPPs including the human immunodeficiency virus type 1 (HIV-1) TAT peptide and oligoarginines are extensively studied and employed. 19 They have been used in conjugation with antimicrobial peptides, 20 standard antibiotics, 21 and nanoparticles 22 for antimicrobial therapy. CPPs have also been used to deliver antibacterial agents to target intracellular bacteria which are otherwise inaccessible by well-known antibiotics such as Gentamicin and Paromomycin.…”