Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes - PubMed (original) (raw)
Comparative Study
Accumulation and intracellular distribution of antitrypanosomal diamidine compounds DB75 and DB820 in African trypanosomes
Amanda M Mathis et al. Antimicrob Agents Chemother. 2006 Jun.
Abstract
The aromatic diamidine pentamidine has long been used to treat early-stage human African trypanosomiasis (HAT). Two analogs of pentamidine, DB75 and DB820, have been shown to be more potent and less toxic than pentamidine in murine models of trypanosomiasis. The diphenyl furan diamidine, DB75, is the active metabolite of the prodrug DB289, which is currently in phase III clinical trials as a new orally active candidate drug to treat first-stage HAT. The new aza analog, DB820, is the active diamidine of the prodrug DB844, currently undergoing preclinical evaluation as a new candidate to treat HAT of the central nervous system. The exact mechanisms of antitrypanosomal activity of aromatic dications remain poorly understood, with multiple mechanisms hypothesized. Pentamidine is known to be actively transported into trypanosomes and binds to DNA within the nucleus and kinetoplast. A long-hypothesized mechanism of action has been that DNA binding ultimately leads to interference with DNA-associated enzymes. Both DB75 and DB820 are intensely fluorescent, which provides an important tool for determining the kinetics of accumulation and intracellular distribution in trypanosomes. We show in the current study that DB75 and DB820 rapidly accumulate and strongly concentrate within trypanosomes, with intracellular concentrations over 15,000-fold higher than mouse plasma concentrations. Both compounds initially accumulate in the DNA-containing nucleus and kinetoplast, but at later time points, they concentrate in non-DNA-containing cytoplasmic organelles. Analyses of the kinetics of uptake and intracellular distribution are necessary to begin to define antitrypanosomal mechanisms of action of DB75, DB820, and other aromatic diamidines.
Figures
FIG. 1.
Chemical structures of DB75, also known as furamidine, and DB820, antitrypanosomal diamidine derivatives of pentamidine.
FIG. 2.
In vitro accumulation of DB75 (▪) and DB820 (▴) over 24 h (n = 3). Trypanosomes were incubated with 7.5 μM of either compound. Concentrations are presented ± SE.
FIG. 3.
Concentration of DB75 (A) and DB820 (B) in S427 trypanosomes and plasma after intravenous administration of 7.5 μmol/kg of DB75 or DB820. Experiments were performed with 3 to 6 mice per time point. Concentrations in trypanosomes were determined based on a volume determination of 58 μm3, as determined by Opperdoes et al. (17). Concentrations are presented ± SE.
FIG. 4.
Fluorescence micrographs of DB75 and DB820 in trypanosomes after 7.5 μmol/kg intravenous dose of either compound. Panels A to E show selected time points from DB75-treated mice, while panels F to J are from DB820-treated mice. In select micrographs, the nucleus is represented by an arrow, the kinetoplast is depicted by an asterisk, and the acidocalcisomes are indicated by an arrowhead.
Similar articles
- Diphenyl furans and aza analogs: effects of structural modification on in vitro activity, DNA binding, and accumulation and distribution in trypanosomes.
Mathis AM, Bridges AS, Ismail MA, Kumar A, Francesconi I, Anbazhagan M, Hu Q, Tanious FA, Wenzler T, Saulter J, Wilson WD, Brun R, Boykin DW, Tidwell RR, Hall JE. Mathis AM, et al. Antimicrob Agents Chemother. 2007 Aug;51(8):2801-10. doi: 10.1128/AAC.00005-07. Epub 2007 May 21. Antimicrob Agents Chemother. 2007. PMID: 17517831 Free PMC article. - Distribution and quantitation of the anti-trypanosomal diamidine 2,5-bis(4-amidinophenyl)furan (DB75) and its N-methoxy prodrug DB289 in murine brain tissue.
Sturk LM, Brock JL, Bagnell CR, Hall JE, Tidwell RR. Sturk LM, et al. Acta Trop. 2004 Jul;91(2):131-43. doi: 10.1016/j.actatropica.2004.03.010. Acta Trop. 2004. PMID: 15234662 - Pharmacokinetic comparison to determine the mechanisms underlying the differential efficacies of cationic diamidines against first- and second-stage human African trypanosomiasis.
Yang S, Wenzler T, Miller PN, Wu H, Boykin DW, Brun R, Wang MZ. Yang S, et al. Antimicrob Agents Chemother. 2014 Jul;58(7):4064-74. doi: 10.1128/AAC.02605-14. Epub 2014 May 5. Antimicrob Agents Chemother. 2014. PMID: 24798280 Free PMC article. - Diamidines for human African trypanosomiasis.
Paine MF, Wang MZ, Generaux CN, Boykin DW, Wilson WD, De Koning HP, Olson CA, Pohlig G, Burri C, Brun R, Murilla GA, Thuita JK, Barrett MP, Tidwell RR. Paine MF, et al. Curr Opin Investig Drugs. 2010 Aug;11(8):876-83. Curr Opin Investig Drugs. 2010. PMID: 20721830 Review. - Diamidines as antitrypanosomal, antileishmanial and antimalarial agents.
Werbovetz K. Werbovetz K. Curr Opin Investig Drugs. 2006 Feb;7(2):147-57. Curr Opin Investig Drugs. 2006. PMID: 16499285 Review.
Cited by
- Structural insights into drug transport by an aquaglyceroporin.
Chen W, Zou R, Mei Y, Li J, Xuan Y, Cui B, Zou J, Wang J, Lin S, Zhang Z, Wang C. Chen W, et al. Nat Commun. 2024 May 11;15(1):3985. doi: 10.1038/s41467-024-48445-4. Nat Commun. 2024. PMID: 38734677 Free PMC article. - Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.
Ungogo MA, de Koning HP. Ungogo MA, et al. Int J Parasitol Drugs Drug Resist. 2024 Aug;25:100533. doi: 10.1016/j.ijpddr.2024.100533. Epub 2024 Mar 30. Int J Parasitol Drugs Drug Resist. 2024. PMID: 38555795 Free PMC article. Review. - Advances in the cellular biology, biochemistry, and molecular biology of acidocalcisomes.
Docampo R. Docampo R. Microbiol Mol Biol Rev. 2024 Mar 27;88(1):e0004223. doi: 10.1128/mmbr.00042-23. Epub 2023 Dec 15. Microbiol Mol Biol Rev. 2024. PMID: 38099688 Review. - Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.
Jamabo M, Mahlalela M, Edkins AL, Boshoff A. Jamabo M, et al. Int J Mol Sci. 2023 Aug 7;24(15):12529. doi: 10.3390/ijms241512529. Int J Mol Sci. 2023. PMID: 37569903 Free PMC article. Review. - Streptococcus pneumoniae Rapidly Translocate from the Nasopharynx through the Cribriform Plate to Invade the Outer Meninges.
Audshasai T, Coles JA, Panagiotou S, Khandaker S, Scales HE, Kjos M, Baltazar M, Vignau J, Brewer JM, Kadioglu A, Yang M. Audshasai T, et al. mBio. 2022 Aug 30;13(4):e0102422. doi: 10.1128/mbio.01024-22. Epub 2022 Aug 4. mBio. 2022. PMID: 35924840 Free PMC article.
References
- Allan, R. A., and J. J. Miller. 1980. Influence of S-adenosylmethionine on DAPI-induced fluorescence of polyphosphate in the yeast vacuole. Can. J. Microbiol. 26:912-920. - PubMed
- Berger, B. J., N. S. Carter, and A. H. Fairlamb. 1995. Characterisation of pentamidine-resistant Trypanosoma brucei brucei. Mol. Biochem. Parasitol. 69:289-298. - PubMed
- Bouteille, B., O. Oukem, S. Bisser, and M. Dumas. 2003. Treatment perspectives for human African trypanosomiasis. Fundam. Clin. Pharmacol. 17:171-181. - PubMed
- Boykin, D. 2002. Antimicrobial activity of the DNA minor groove binders furamidine and analogs. J. Braz. Chem. Soc. 13:763-771.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources