| The human pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, possesses a unique, impenetrable cell wall important to the bacilli's lifecycle. Indeed, many Mtb cell wall metabolites have been implicated as virulence factors that create a passive barrier for protection against host effector molecules and actively communicate with host cells. One of the more complex families of Mtb cell wall metabolites are the sulfatides. Sulfolipid-1 (SL-1), the most abundant sulfatide, is a trehalose-based glycolipid located on the outer surface layer of Mtb. Provocatively, SL-1 is unique to pathogenic mycobacteria and its amounts positively correlate with strain virulence. The linkage between SL-1 and Mtb virulence inspired a search for the biological activity of SL-1, which for over the past fifty years has attributed numerous, albeit conflicting, biological activities to this metabolite. However, no direct role for SL-1 in Mtb pathogenesis has been established.;The work presented here seeks to define the effects of SL-1 and its sulfated intermediates on Mtb pathogenesis. Chapter Two describes methods developed to isolate and purify sulfated metabolites, such as SL-1, as natural products from Mtb. Next, purified SL-1 and a strain of Mtb engineered to lack SL-1 (Deltastf0) are utilized to examine the molecule's biological function using cell-based infection models (Chapter Three). Interestingly, Delta stf0 exhibits augmented survival in human macrophages coupled with increased resistance to cationic antimicrobial peptides. Chapter Four investigates the biological activity of the recently characterized SL-1 intermediate, SL 659. Surprisingly, SL659 demonstrates potent immunomodulatory activity on immune system cells in vitro. |
