Uridine diphosphate N-acetyl muramic acid (UDP NAM) is a critical intermediate in bacterial peptidoglycan (PG) biosynthesis.  As the primary  source of muramic acid that comprises the PG backbone, modifications installed at the UDP NAM intermediate can be used to selectively tag and manipulate this polymer via metabolic incorporation. However, synthetic and purification strategies to access large quantities of UDP NAM, as well as their derivatives, prove challenging or unprecedented until this work. A robust chemoenzymatic synthesis was developed to expand the UDP NAM substrate scope beyond N-acetyl azides and alkynes. The synthesis reveals that the bacterial cell wall recycling enzymes MurNAc/GlcNAc anomeric kinase (AmgK) and NAM α-1 phosphate uridyl transferase (MurU)  were permissive to large permutations in the sugar donor.  We further explored the utility of these NAMs and UDP NAMs in the fluorescent labeling of both Gram (-) and Gram (+) peptidoglycan in whole cells using a variety of bioorthogonal chemistries.  This report allows for rapid and scalable access to a variety of functionalized NAMs and UDP NAMs, which now can be used in tandem with other complimentary bioorthogonal labeling strategies to address fundamental questions surrounding PG’s role in immunology and microbiology .<br/>

Chemoenzymatic synthesis of peptidoglycan building blocks for cell wall remodeling

256th National Meeting (2018)

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