A new class of synthetic antibacterials acting on lipopolysaccharide biosynthesis

Abstract

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.

Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

“…2) (10). However, none of the 2␤-deoxy-Kdo derivatives were capable of crossing the inner membrane and reaching the KdsB enzyme in the cytoplasm and consequently showed no in vivo activity (11,12). The design of new, improved inhibitors of KdsB that are capable of crossing the cytoplasmic membrane has been limited by the lack of detailed kinetic and structural information on the enzyme.…”

Crystal structure of the dipeptide binding protein from Escherichia coli involved in active transport and chemotaxis

“…The combination of genetics and now structure paves the way for a fuller understanding of how a wide variety of peptides are bound with high affinity. The binding site is also an attractive target for structure-based drug design, because antibiotics attached to a dipeptide backbone are known to enter the cell via the dipeptide permease (Hammond et al, 1987). Designing antibiotics for uptake by the dipeptide permease has the advantage that the bacteria should respond to the antibiotic as if it were an attractant.…”

Toxicity of oxalysine and oxalysine-containing peptides against Candida albicans: regulation of peptide transport by amino acids

“…Basrai and others Kingsbury et al, 1983;Lichliter et al, 1976;MeyerGlauner et al, 1982;Milewski et al, 1991a). An understanding of the number of peptide permeases in C. albicans and their regulation under different physiological conditions is clearly important in order to design and deliver an efficacious, pathogen-specific drug via 'illicit transport' (Fickel & Gilvarg, 1973;Ames et al, 1973;Hammond et al, 1987;Higgins, 1987) to this opportunistic pathogen. Previous investigations have concluded that the peptide transport system of C .…”