Volume 28, Issue 3 pp. 370-377

Full Access

Rapid In Vitro Prescreen for Chelators as Potential Trypanocides Based on Growth of Crithidia fasciculata1

ANNA SHAPIRO,

ANNA SHAPIRO

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

S. H. HUTNER,

S. H. HUTNER

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

LILLIAN KATZ,

LILLIAN KATZ

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

C. J. BACCHI,

C. J. BACCHI

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

ANNA SHAPIRO,

ANNA SHAPIRO

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

S. H. HUTNER,

S. H. HUTNER

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

LILLIAN KATZ,

LILLIAN KATZ

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

C. J. BACCHI,

C. J. BACCHI

Haskins Laboratories and Biology Department, Pace University, Pace Plaza, New York, New York 10038

Search for more papers by this author

First published: August 1981

https://doi.org/10.1111/j.1550-7408.1981.tb02869.x

Citations: 12

^†

Investigation supported by NIH grants AI13801 (S.H.H.) and AI13852 (C.J.B.); a grant from the Special Programme U.N.D.P., World Bank/World Health Organization (S.H.H.), and U.S. Public Health Service grant FR-05596 (A. M. Liverman, Haskins Laboratories). The authors thank Ms. Barbara Ellenbogen for her help in preparing the manuscript; Dr. B. van't Riet, Dr. W. E. Scott, and Proctor & Gamble, Inc., for samples.

About

PDF

Tools

Share a link

Email
Wechat
Bluesky

ABSTRACT

A rapid in vitro prescreen for Fe-binding chelators has been developed with growth of Crithidia fasciculata and the sparing of its heme requirement in a defined medium as a test system. The prescreen functions as an index of chelator-mediated Fe transport and as an index of growth inhibition, presumably by the interference with Fe and/or heme metabolism at intracellular chelatable sites. Of 161 chelators examined, 84 were active heme-sparers; 32 of these inhibited growth at low chelator concentrations. Twenty-eight other chelators inhibited growth and another 49 were inactive. Such chelating activity directed at Fe and heme targets in hemoflagellates may provide leads for chemotherapy.

LITERATURE CITED

1 Aisen, P. & Leibman, A. 1977. Transport of iron by transferrin, in R. F. Gould, ed., Bioinorganic Chemistry II, Am. Chem. Soc., Washington , D.C .
Google Scholar
2 Amole, B. O. & Clarkson, A. B., Jr. 1981. Trypanosoma brucei: host parasite interaction in parasite destruction of salicylhydroxamic acid and glycerol in mice. Exp. Parasitol., 51: 133–140.
10.1016/0014-4894(81)90050-3
CAS PubMed Web of Science® Google Scholar
3 Apted, F. I. C. 1980. Present status of chemotherapy and chemoprophylaxis of human trypanosomiasis in the Eastern Hemisphere. Pharmacol. Ther., 11: 391–413.
10.1016/0163-7258(80)90035-2
CAS PubMed Web of Science® Google Scholar
4 Baker, H., Frank, O., Shapiro, A. & Hutner, S. H. 1980. Assay of unconjugated pteridines in biological fluids and tissues with Crithidia, in S. P. Colowick & N. O. Kaplan, eds., Methods in Enzymology. Vitamins and Coenzymes, Academic Press, 66E: 490–500.
10.1016/0076-6879(80)66492-1
Google Scholar
5 Clarkson, A. B. & Brohn, F. H. 1976. Trypanosomiasis: an approach to chemotherapy by the inhibition of carbohydrate catabolism. Science, 194: 204–206.
10.1126/science.986688
CAS PubMed Web of Science® Google Scholar
6 Elford, H. L., Wampler, G. L. & van't Riet, B. 1979. New ribonucleotide reductase inhibitors with antineoplastic activity. Cancer Res., 39: 844–851.
CAS PubMed Web of Science® Google Scholar
7 Evans, D. A. & Brown, D. C. 1973. The inhibitory effect of aromatic hydroxamic acids on the cyanide-insensitive terminal oxidase of Trypanosoma brucei. Trans. R. Soc. Trop. Med. Hyg., 67: 258.
10.1016/0035-9203(73)90160-0
CAS PubMed Web of Science® Google Scholar
8 Fairlamb, A. H. & Bowman, I. B. R. 1977. Inhibitor studies on particulate sn-glycerol-3-phosphate oxidase from Trypanosoma brucei. Int. J. Biochem., 8: 669–675.
10.1016/0020-711X(77)90105-7
CAS Web of Science® Google Scholar
9 Goodwin, L. G. 1980. New drugs for old diseases. Trans. R. Soc. Trop. Med. Hyg., 74: 1–7.
10.1016/0035-9203(80)90002-4
CAS PubMed Web of Science® Google Scholar
10 Grady, R. W., Graziano, J., Akers, H. A. & Cerami, A. 1976. The development of new iron-chelating drugs. J. Pharmacol. Exp. Ther., 196: 478–485.
CAS PubMed Web of Science® Google Scholar
11 Hanka, L. J., Martin, D. G. & Neil, G. L. 1978. In vitro methods used in detection and quantitation of antitumor drugs produced by microbial fermentation. Lloydia, 41: 85–97.
CAS PubMed Web of Science® Google Scholar
12 Hoy, T., Humphrys, J., Jacobs, A., Williams, A. & Poňka, P. 1979. Effective iron chelation following oral administration of an isoniazid-pyridoxal hydrazone. Br. J. Haematol., 43: 443–449.
10.1111/j.1365-2141.1979.tb03771.x
CAS PubMed Web of Science® Google Scholar
13 Hutner, S. H., Bacchi, C. J. & Baker, H. 1979. Nutrition of the Kinetoplastida, in W. H. R. Lumsden & D. A. Evans, eds., Biology of the Kinetoplastida, Academic Press, New York , 2: 653–691.
Google Scholar
14 Kochan, I. 1977. Role of siderophores in nutritional immunity and bacterial parasitism, in F. D. Weinberg, ed., Microorganisms and Minerals, Marcel Dekker, Inc., New York , Basel .
Google Scholar
15 Lardy, H. 1978. Ferroactivator protein permits ferrous ion to stimulate phosphoenolpyruvate carboxykinase, in D. L. Dutton, J. S. Leigh & S. Scarpa, eds., Frontiers of Biological Energetics. Electrons to Tissues, Academic Press, New York , 2: 1003–1010.
10.1016/B978-0-12-225402-4.50031-0
Google Scholar
16 Neilands, J. B. 1979. Biomedical and environmental significance of siderophores, in N. Kharasch, ed., Trace Metals in Health and Disease, Raven Press, New York , pp. 27–41.
Google Scholar
17 Njogu, R. M., Whittaker, C. J. & Hill, G. C. 1980. Evidence for a branched electron transport chain in Trypanosoma brucei. Mol. Biochem. Parasitol., 1: 13–30.
10.1016/0166-6851(80)90038-9
CAS PubMed Web of Science® Google Scholar
18 Payne, S. M. & Finkelstein, R. A. 1978. The critical role of iron in host-bacterial interactions. J. Clin. Invest., 62: 1428–1440.
10.1172/JCI109062
Web of Science® Google Scholar
19 Poňka, P., Borová, J., Neuwirt, J., Fuchs, O. & Nečas, E. 1979. A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochim. Biophys. Acta, 586: 278–297.
10.1016/0304-4165(79)90100-4
CAS PubMed Web of Science® Google Scholar
20 Sandell, E. B. & Onishi, O. 1979. Photometric Determination of Traces of Metals. General Aspects. John Wiley, New York .
Google Scholar
21a Shapiro, A., Bacchi, C. J., Nathan, H., Garafolo, J., Dittus, S., Rescigno, D. & Hutner, S. H. 1980. Novel chelators for Trypanosoma brucei chemotherapy. J. Protozool., 27: 34A.
Google Scholar
21b Shapiro, A., Hutner, S. H., Katz, L., Bacchi, C. J., Tamburro, K. O. & Baker, H. 1978. Dense Crithidia growth and heme sparing: relation to Fe, Cu, Mo chelation. J. Protozool., 25: 530–535.
10.1111/j.1550-7408.1978.tb04180.x
CAS PubMed Web of Science® Google Scholar
22 Shapiro, A., Katz, L., Hutner, S. H., Harracksingh, C. & Bacchi, C. J. 1980. Crithidia media as guide to antihaemoflagellate chemotherapy aimed at porphyrin and transitional metal metabolism, in D. S. Rowe & H. Hirumi, eds., The In Vitro Cultivation of the Pathogens of Tropical Diseases (Trop. Dis. Res. Ser. No. 3), Schwabe & Co., Basel , Switzerland , pp. 410–415.
Google Scholar
23 van't Riet, B., Kier, L. & Elford, A. L. 1980. Structure-activity relationships of benzohydroxamic inhibitors of ribonucleotide reductase. J. Pharm. Sci., 69: 100–103.
10.1002/jps.2600690731
Google Scholar
24 Wagner, W.-H. 1980. Drugs for tropical diseases in the Third World. Interdiscip. Sci. Rev., 5: 186–203.
10.1179/030801880789767657
CAS Web of Science® Google Scholar
25 Weinberg, E. D. 1978. Iron and infection. Microbiol. Rev., 42: 45–66.
10.1128/mr.42.1.45-66.1978
CAS PubMed Web of Science® Google Scholar
26 Werbel, L. M., Worth, D. F. & Weitzel, S. M. 1979. Antiparasitic agents. Annu. Rev. Med. Chem., 14: 122–131.
10.1016/S0065-7743(08)61358-5
CAS Google Scholar
27 Williamson, J. & Scott-Finnegan, T. J. 1978. Trypanocidal activity of antitumor antibiotics and other metabolic inhibitors. Antimicrob. Agents Chemother., 13: 735–744.
10.1128/AAC.13.5.735
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume28, Issue3

August 1981

Pages 370-377

Rapid In Vitro Prescreen for Chelators as Potential Trypanocides Based on Growth of Crithidia fasciculata1

ABSTRACT

LITERATURE CITED

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Rapid In Vitro Prescreen for Chelators as Potential Trypanocides Based on Growth of Crithidia fasciculata1

ABSTRACT

LITERATURE CITED

Citing Literature

References

Related

Information