Murgocil is a Highly Bioactive Staphylococcal-Specific
Inhibitor of the Peptidoglycan Glycosyltransferase Enzyme MurG
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Abstract
Modern
medicine is founded on the discovery of penicillin and subsequent
small molecules that inhibit bacterial peptidoglycan (PG) and cell
wall synthesis. However, the discovery of new chemically and mechanistically
distinct classes of PG inhibitors has become exceedingly rare, prompting
speculation that intracellular enzymes involved in PG precursor synthesis
are not ‘druggable’ targets. Here, we describe a β-lactam
potentiation screen to identify small molecules that augment the activity
of β-lactams against methicillin-resistant Staphylococcus
aureus (MRSA) and mechanistically characterize a compound
resulting from this screen, which we have named murgocil. We provide
extensive genetic, biochemical, and structural modeling data demonstrating
both <i>in vitro</i> and in whole cells that murgocil specifically
inhibits the intracellular membrane-associated glycosyltransferase,
MurG, which synthesizes the lipid II PG substrate that penicillin
binding proteins (PBPs) polymerize and cross-link into the cell wall.
Further, we demonstrate that the chemical synergy and cidality achieved
between murgocil and the β-lactam imipenem is mediated through
MurG dependent localization of PBP2 to the division septum. Collectively,
these data validate our approach to rationally identify new target-specific
bioactive β-lactam potentiation agents and demonstrate that
murgocil now serves as a highly selective and potent chemical probe
to assist our understanding of PG biosynthesis and cell wall biogenesis
across Staphylococcal species