A new class of synthetic antibacterials acting on lipopolysaccharide biosynthesis

Although there is a need for antibacterial agents that act only on Gram-negative bacteria, there are at present few such compounds. The 2-deoxy analogue of beta-KDO (3-deoxy-beta-D-manno-2-octulopyranosonic acid) is a potent inhibitor of a key enzyme (CMP-KDO synthetase) in lipopolysaccharide biosynthesis of Gram-negative bacteria, but it fails to penetrate intact bacteria. Coupling an L-L-dipeptide to the 8-amino-2,8-dideoxy analogue of beta-KDO enabled it to be recognized and actively accumulated by certain peptide permeases of the cytoplasmic membrane. The dipeptide was hydrolysed in the cell and the inhibitor released. Subsequent inhibition of CMP-KDO synthetase led to the accumulation of large amounts of lipid A precursor and bacterial death. These compounds represent a new class of synthetic antimicrobials with a novel mechanism of action and considerable potential as chemotherapeutic agents.