The goal of this research is to study the antiinfective agents present in unusual sources, notably higher plant extracts (and of molecules inspired by them), in order to discover new chemical entities with novel modes of action and to determine their potential for use in human medicine. Novel antibiotics are specially sought for the treatment of troublesome viral infections against which contemporary antibiotics are not fully satisfactory because of toxicity, low potency, narrow spectrum, resistance, poor pharmacokinetics, or the like. Central to this effort is the exploration of extracts of suitable botanically identified plants (including those with a folkloric reputation for use as antiinfectives), extraction, screening in vitro against HIV and BIV viruses, bioassay directed fractionation, physico-chemical structure determination, synthesis of analogs (where indicated for structural clarification, preparation of substantial quantities for evaluation, optimization of activity, etc.), evaluation of in vitro antiinfective spectrum in comparison with established agents, and in vivo evaluation in infected experimental animals for the most likely candidates. The latter is done off-site by pharmaceutical firms possessing the special facilities and expertise for this work. Investigation of the molecular mode of action of the quinolones and their interaction with DNA and DNAgyrase was notably successful in earlier versions of this application and these studies will be continued. The fluoroquinolones are among the most widely investigated contemporary antibiotics. Six are marketed in the US, another dozen are approaching marketing decisions and many more are less advanced. One of the quinolones prepared in an earlier version of this grant (levoxacin) is notably active against bacteria causing death to HIV sufferers and is under clinical trial in Japan and the US. We have elaborated and are testing successfully a theory of the molecular mode of action of these agents and this theory is guiding successful design of new chemical entities. Further examination of this theory is proposed as is extension to possible application against the fungal and mammalian enzymes so as to extend or shift the spectrum of contemporary quinolones to include other organisms dangerous to HIV sufferers and to the treatment of cancer. Alternative proposals to rationalize the molecular mode of action of quinolones are also under investigation. Attempts to broaden these investigations to mammalian DNA topoisomerase II are also in progress. The need for modern screening activity is particularly pressing as pressure on tropical biota, alternate land use schemes, and other societal changes in the Third World countries make tropical species and indigenous medical systems increasingly vulnerable.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI013155-17A3
Application #
3125403
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1976-09-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
17
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
Schools of Pharmacy
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Mitscher, L A; Baker, W (1998) Tuberculosis: a search for novel therapy starting with natural products. Med Res Rev 18:363-74
Mitscher, L A; Jung, M; Shankel, D et al. (1997) Chemoprotection: a review of the potential therapeutic antioxidant properties of green tea (Camellia sinensis) and certain of its constituents. Med Res Rev 17:327-65
Gollapudi, S R; Telikepalli, H; Jampani, H B et al. (1994) Alectosarmentin, a new antimicrobial dibenzofuranoid lactol from the lichen, Alectoria sarmentosa. J Nat Prod 57:934-8
Devasthale, P V; Mitscher, L A; Telikepalli, H et al. (1992) Dactylocyclines, novel tetracycline derivatives produced by a Dactylosporangium sp. III. Absolute stereochemistry of the dactylocyclines. J Antibiot (Tokyo) 45:1907-13
Mitscher, L A; Drake, S; Gollapudi, S R et al. (1987) A modern look at folkloric use of anti-infective agents. J Nat Prod 50:1025-40
Mitscher, L A (1987) Chemistry of newer antibiotics directed toward overcoming bacterial resistance. Bull N Y Acad Med 63:269-94
Boger, D L; Yasuda, M; Mitscher, L A et al. (1987) Streptonigrin and lavendamycin partial structures. Probes for the minimum, potent pharmacophore of streptonigrin, lavendamycin, and synthetic quinoline-5,8-diones. J Med Chem 30:1918-28
Mitscher, L A; Drake, S; Gollapudi, S R et al. (1986) Isolation and identification of higher plant agents active in antimutagenic assay systems: Glycyrrhiza glabra. Basic Life Sci 39:153-65
Boger, D L; Mitscher, L A; Mullican, M D et al. (1985) Antimicrobial and cytotoxic properties of 9,10-dihydrophenanthrenes: structure-activity studies on juncusol. J Med Chem 28:1543-7