Projects per year
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 language | English |
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Pages (from-to) | 4699-4706 |
Number of pages | 8 |
Journal | Antimicrobial Agents and Chemotherapy |
Volume | 57 |
Issue number | 10 |
DOIs | |
Publication status | Published - 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.
Projects
- 4 Finished
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Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R., Fairlamb, A., Ferguson, M., Field, M., Gilbert, I., Gray, D., Hopkins, A., Horn, D., Read, K., Wyatt, P. & van Aalten, D.
1/02/11 → 1/07/17
Project: Research
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Clinical PhD Programme: Meghan Perry
Cantrell, D., Fairlamb, A., Lambert, J. & Marshall, S.
7/09/09 → 6/10/14
Project: Research
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Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A., Ferguson, M. & Frearson, J.
1/01/08 → 31/12/12
Project: Research
Student Theses
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The metabolism of bicyclic nitro drugs in Leishmania
Author: Norval, S., 2016Supervisor: Read, K. (Supervisor) & Fairlamb, A. (Supervisor)
Student thesis: Doctoral Thesis › Doctor of Philosophy