Design and synthesis of peptide derivatives of a 3-deoxy-D-manno-2-octulosonic acid (KDO) analog as novel antibacterial agents acting upon lipopolysaccharide biosynthesis

Abstract

On the basis of the knowledge that the amino acid 3 (8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid) is a potent inhibitor of 3-deoxy-manno-octulosonate cytidylyltransferase, attempts were made to design derivatives that would act as antibacterials against Gram-negative bacteria by inhibiting lipopolysaccharide biosynthesis. Compound 3 and the derivatives 15 and 16 containing an additional amino acid were not lethal to bacteria. However, compounds 17-22, which contain a N-terminally linked dipeptide, exhibited good antibacterial activity in vitro on testing against strains of the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. They have no activity against Gram-positive bacteria such as Staphylococcus aureus.

ATP-Binding Cassette Transporters Are Targets for the Development of Antibacterial Vaccines and Therapies

“…Artificially created drugs, in which the antibacterial compound is linked to the natural substrate for the transporter, have been referred to as smugglins (60) and have been proposed for several decades. Several reports have indicated the feasibility of developing such drugs, and many of these drugs appear to exploit peptide ABC transporters, such as the OppA or DppA systems (15,23,26,31,69,71). One of the most elegant examples of this approach involved the synthesis of an analogue of 3-deoxy-D-manno-2-octulosonic acid attached to a dipeptide.…”

“…One of the most elegant examples of this approach involved the synthesis of an analogue of 3-deoxy-D-manno-2-octulosonic acid attached to a dipeptide. The resulting compound was active against gram-negative bacteria and had the ability to block the linking of lipid A to the core polysaccharide of lipopolysaccharide (15,26). More recently, Marshall et al reasoned that the potential antibacterial compound N 3 -(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid might be linked to a peptide taken up by the DppA or OppA systems (49).…”

New Targets for Antibacterial Design: Kdo Biosynthesis and LPS Machinery Transport to the Cell Surface

“…19) as a new class of Kdo analogues potential inhibitors of CMP-Kdo synthetase. [157][158][159]. Unfortunately, also amino acid 54, permeated poorly across the bacterial cell envelope; this observation suggested that the linkage of peptides to 62 could produce a compound resembling a natural substrate for the bacterial permeases.…”

“…The peptide derivatised prodrug was subsequently metabolized by endogenous bacterial aminopeptidases in the cytoplasm to release the active form of the inhibitor. Of these dipeptide prodrugs, alanylalanyl, norvalylalanyl and arginylnorvalyl derivatives (55-57) exhibited good antibacterial activity in vitro against the Salmonella and E. coli strains [159]. It is also revealed that virulent strains of Salmonella typhimurium become avirulent by inhibition of CMP-Kdo synthase which stops LPS synthesis, accumulates lipid A precursor in the outer membrane and causes structural perturbations [160,161].…”

Localization of the enzyme 3-deoxy-d-manno-2-octulosonic acid aldolase

“…Because Gramnegative bacteria were found not to be viable in the absence of the K D O residue (Rick and Osborn 1972), KDO seems to be an important target for the development of a special drug (Goldmann et al 1987). Claesson et al (1987) has already tested some KDO derivatives as inhibitors for enzymatic cell wall assembly.…”