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

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Published inAntimicrobial Agents and Chemotherapy Vol. 57; no. 10; pp. 4699 - 4706
Main Authors PATTERSON, Stephen, WYLLIE, Susan, STOJANOVSKI, Laste, PERRY, Meghan R, SIMEONS, Frederick R. C, NORVAL, Suzanne, OSUNA-CABELLO, Maria, DE RYCKER, Manu, READ, Kevin D, FAIRLAMB, Alan H
Format Journal Article
LanguageEnglish
Published Washington, DC American Society for Microbiology 01.10.2013
Subjects
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiprotozoal Agents
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Antitubercular Agents
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Biological and medical sciences
Experimental Therapeutics
Female
Human protozoal diseases
Infectious diseases
Leishmania donovani
Leishmaniasis, Visceral
Leishmaniasis, Visceral - drug therapy
Leshmaniasis
Medical sciences
Mice
Mice, Inbred BALB C
Mycobacterium tuberculosis
Nitroimidazoles - chemistry
Nitroimidazoles - pharmacology
Nitroimidazoles - therapeutic use
Parasitic diseases
Pharmacology. Drug treatments
Protozoal diseases
Stereoisomerism
Infection
Drug
Protozoal disease
Treatment
Enantiomer
Oral administration
Kala azar
Antituberculous agent
Leishmaniasis
Parasitosis
Antibacterial agent
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Abstract OA  Classifications Services AAC Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue AAC About AAC Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy AAC RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0066-4804 Online ISSN: 1098-6596 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to AAC .asm.org, visit: AAC       
AbstractList 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.
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.
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.
OA  Classifications Services AAC Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue AAC About AAC Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy AAC RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0066-4804 Online ISSN: 1098-6596 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to AAC .asm.org, visit: AAC       
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.
Author Maria Osuna-Cabello
Manu De Rycker
Susan Wyllie
Laste Stojanovski
Frederick R. C. Simeons
Alan H. Fairlamb
Kevin D. Read
Meghan R. Perry
Stephen Patterson
Suzanne Norval
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  surname: DE RYCKER
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Issue 10
Keywords Infection
Drug
Protozoal disease
Treatment
Enantiomer
Oral administration
Kala azar
Antituberculous agent
Leishmaniasis
Parasitosis
Antibacterial agent
Language English
License CC BY 4.0
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PublicationTitle Antimicrobial Agents and Chemotherapy
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The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in...
ABSTRACT The novel nitroimidazopyran agent ( S )-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is...
The novel nitroimidazopyran agent ( S )-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in...
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SubjectTerms Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiprotozoal Agents
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Antitubercular Agents
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Biological and medical sciences
Experimental Therapeutics
Female
Human protozoal diseases
Infectious diseases
Leishmania donovani
Leishmaniasis, Visceral
Leishmaniasis, Visceral - drug therapy
Leshmaniasis
Medical sciences
Mice
Mice, Inbred BALB C
Mycobacterium tuberculosis
Nitroimidazoles - chemistry
Nitroimidazoles - pharmacology
Nitroimidazoles - therapeutic use
Parasitic diseases
Pharmacology. Drug treatments
Protozoal diseases
Stereoisomerism
Title The R Enantiomer of the Antitubercular Drug PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis
URI http://aac.asm.org/content/57/10/4699.abstract
https://www.ncbi.nlm.nih.gov/pubmed/23856774
https://journals.asm.org/doi/10.1128/AAC.00722-13
https://search.proquest.com/docview/1433273886
https://search.proquest.com/docview/1443378905
https://pubmed.ncbi.nlm.nih.gov/PMC3811480
Volume 57
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