The bacterial enzyme UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase
(LpxC), catalyzing the first committed step of lipid A biosynthesis, represents a promising target
in the development of novel antibiotics against Gram-negative bacteria. Structure, catalytic reaction
mechanism and regulation of the Zn2+-dependent metalloamidase have been intensively investigated.
The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology
with any mammalian protein, but is highly conserved in Gram-negative bacteria, thus permitting
the development of Gram-negative selective antibacterial agents with limited off-target effects. Several smallmolecule
LpxC inhibitors have been developed, like the substrate analog TU-514 (12a), the aryloxazoline L-161,240
(13w), the sulfonamide BB-78485 (23a), the N-aroyl-L-threonine derivative CHIR-090 (24a), the sulfone-containing pyridone
LpxC-3 (43e), and the uridine-based inhibitor 1-68A (47a), displaying diverse inhibitory and antibacterial activities.
Most of these compounds share a Zn2+-binding hydroxamate moiety attached to a structural element addressing the hydrophobic
tunnel or the UDP binding site. The butadiynyl derivative ACHN-975 (28) is the first LpxC inhibitor entering