Syntheses around the Transglycosylation Step in Peptidoglycan Biosynthesis

The molecular biology of moenomycins: towards novel antibiotics based on inhibition of bacterial peptidoglycan glycosyltransferases

“…Since natural products produced by microorganisms and plants evolved to function in environments very different from that of the human body, their structures often need to be modified to improve in vivo activity and/or pharmacology. Although chemical synthesis has been widely used to achieve such structural improvements (Welzel, 2005), biology-based approaches to manipulate complicated natural product chemistry are now competitive with these chemical methodologies in many cases (Chen et al, 2003). In these approaches, genes or enzymes for natural product biosynthesis are 'mixed' to generate novel metabolic pathways, ultimately leading to a library of closely related compounds.…”

“…Despite the unique structure and mode of action of MmA (Ostash and Walker, 2005), the compound has poor pharmokinetics, and no moenomycin-based antibiotics are used clinically. This is because the chemical synthesis of Mm's is a daunting task (Welzel, 2005;Taylor et al, 2006) and the biosynthetic genes were only recently discovered (Ostash et al, 2007). Advances in understanding the genetics of MmA production provide new tools to produce structurally complex moenomycin derivatives as well as to unravel the details of how bacteria regulate production and resistance to such potent antibiotics.…”

“…The MmA pentasaccharide moiety contains heavily modified sugars and is further decorated with a pentacyclic chromophore, unit A (Figure 1). A phosphoglycerate, unit G, joins the pentasaccharide and lipid portions of MmA and is the most unique structural characteristic of the phosphoglycolipids (Welzel, 2005). Naturally occurring moenomycins differ mainly in the structure of carbohydrate unit F (attached to phosphoglycerate; Figure 1) and the lipid moiety.…”

“…Other Mm derivatives lack the chromophore unit A or unit D sugar. Many of the known phosphoglycolipid antibiotics were isolated three to four decades ago and their exact chemical structures are not known (Welzel, 2005).…”

“…Thus, a mutation that would decrease the binding efficiency of MmA is likely to inactive the PGT. Previous attempts at modifying the E and F sugars or the phosphoglycerate unit itself have resulted in a loss of activity (Welzel, 2005). These core interactions add the most specificity to the Mm's.…”