Studies on (beta,1 -> 5) and (beta,1 -> 6) linked octyl Gal(f) disaccharides as substrates for mycobacterial galactosyltransferase activity

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberc ulosis (MTB) and the continuing pandemic of tuberculosis emphasizes the urg ent need for the development of new, anti-tubercular agents with novel drug targets. The recent structural elucidation of the mycobacterial cell wall highlights a large variety of structurally unique components that may be a basis for new drug development. This publication describes the synthesis, c haracterization, and screening of several octyl Galf(beta ,1 -->5)Galf and octyl Galf(beta ,1 -->6)Galf derivatives. A cell-free assay system has been utilized for galactosyltransferase activity using UDP[C-14]Galf as the gly cosyl donor, and in vitro inhibitory activity has been determined in a colo rimetric broth microdilution assay system against MTB H37Ra and three clini cal isolates of Mycobacterium avium complex (MAC). Certain derivatives show ed moderate activities against MTB and MAC. The biological evaluation of th ese disaccharides suggests that more hydrophobic analogues with a blocked r educing end showed better activity as compared to totally deprotected disac charides that more closely resemble the natural substrates in cell wall bio synthesis. (C) 2001 Elsevier Science Ltd. All rights reserved.