The R Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis

Stephen Patterson, Susan Wyllie, Laste Stojanovski, Meghan R. Perry, Frederick R. C. Simeons, Suzanne Norval, Maria Osuna-Cabello, Manu De Rycker, Kevin D. Read (Lead / Corresponding author), Alan H. Fairlamb (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clinical trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA-824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with >99% suppression of parasite burden when administered orally at 100 mg kg of body weight(-1), twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL.
    Original languageEnglish
    Pages (from-to)4699-4706
    Number of pages8
    JournalAntimicrobial Agents and Chemotherapy
    Volume57
    Issue number10
    DOIs
    Publication statusPublished - Oct 2013

    Fingerprint Dive into the research topics of 'The <em>R</em> Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis'. Together they form a unique fingerprint.

  • Student Theses

    The metabolism of bicyclic nitro drugs in Leishmania

    Author: Norval, S., 2016

    Supervisor: Read, K. (Supervisor) & Fairlamb, A. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Cite this