Antimycobacterial activity of peptide conjugate of pyridopyrimidine derivative against Mycobacterium tuberculosis in a series of in vitro and in vivo models

Kata Horváti, Bernadett Bacsa, Nóra Szabó, Kinga Fodor, Gyula Balka, Miklós Rusvai, Éva Kiss, Gábor Mezo, Vince Grolmusz, Beáta Vértessy, Ferenc Hudecz, Szilvia Bosze

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

New pyridopyrimidine derivatives were defined using a novel HTS in silico docking method (FRIGATE). The target protein was a dUTPase enzyme (EC 3.6.1.23; Rv2697) which plays a key role in nucleotide biosynthesis of Mycobacterium tuberculosis (Mtb). Top hit molecules were assayed in vitro for their antimycobacterial effect on Mtb H37Rv culture. In order to enhance the cellular uptake rate, the TB820 compound was conjugated to a peptid-based carrier and a nanoparticle type delivery system (polylactide-co-glycolide, PLGA) was applied. The conjugate had relevance to in vitro antitubercular activity with low in vitro and in vivo toxicity. In a Mtb H37Rv infected guinea pig model the in vivo efficacy of orally administrated PLGA encapsulated compound was proven: animals maintained a constant weight gain and no external clinical signs of tuberculosis were observed. All tissue homogenates from lung, liver and kidney were found negative for Mtb, and diagnostic autopsy showed that no significant malformations on the tissues occurred.

Original languageEnglish
Pages (from-to)S207-S211
JournalTuberculosis
Volume95
Issue numberS1
DOIs
Publication statusPublished - Jun 1 2015

Keywords

  • Guinea pig infection model
  • In silico docking
  • PLGA encapsulation
  • Peptide conjugate
  • Pyridopyrimidines

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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