Our research efforts concern mycobacterial lipids that have demonstrated or putative relevance to virulence in pathogenic species with the goal of increasing our understanding of the molecular and cellular mechanisms through wihch these substances may participate in the disease process. We will seek to find and establish the structures of: cord factor (trehalose dimycolate) and of a probable phthiocerol dimycocerosate (DIM) of M. leprae from infected armadillos; to establish the structure of a new (probable precursor) attenuation indicator lipid (AIL) of phage type I strains of M. tuberculosis; and to define the biosynthetic lesion in attenuated DIM-less mutants of M. tuberculosis. Our collaborative discovery of new classes of serologically active specifically plycosylated C-mycosides in the M. avium -intracellular - scrofulaceum complex, provides a spectrum of these glycolipids for studying their behavior as receptor substances for mycobacteriophage D4, in order to determine the effects of the carbohydrate adornments. We shall also seek to define the minimal structure required for receptor activity. We will also undertake collaborative studies with colleagues to delineate the biosynthesis pathways of these glycosylated C-mycosides, since they are surprisingly simple, with specific structural features for each serotype. Problems relevant to inhibition of phagosome-lysosome fusion in macrophages by a spectrum of M. tuberculosis species will be studied by electron microscopy to probe the influence of sulfatides, strongly acidic lipids, DIM, and AIL on this process. A fruitful program developed for the synthesis of analogs of cord factor will be expanded to provide a unique spectrum of pseudo cord factors whose biological activities will be determined in order to define the intimate relations of glycolipid structures to biological activites: Toxicity, granulomagenicity, adjuvant activity, influence on macrophages, and antitumor properties. Some synthetic pseudo cord factors that we have developed already show promise as substitutes for natural cord factors in experimental tumor immunotherapy.
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