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

Abstract

Lipopolysaccharide (LPS), which constitutes the lipid portion of the outer leaflet of Gram-negative bacteria, is essential for growth. It is also responsible for the variety of biological effects associated with Gram-negative sepsis. Recent advances have elucidated the exact chemical structure of this highly complex macromolecule and much of the enzymology involved in its biosynthesis. Enzymes involved in LPS biogenesis are optimal targets for the development of novel therapeutics since they are sufficiently conserved among diverse, clinically-relevant bacteria and no analogue counterpart is present in humans. During the last thirty years a number of inhibitors of LPS biosynthesis have been developed: some of these compounds have antibacterial properties, while others show excellent in vitro activity and are undergoing further investigation. The main focus of this review will be the biology of LPS in bacteria summarizing the knowledge about structure and enzymatic catalysis, as well as chemical efforts towards the synthesis of inhibitors of the key enzymes involved in the biosynthesis of Kdo, toward the minimal conserve structure Kdo(2)-LipA. In addition, very recent advances in deciphering the molecular mechanisms of LPS transport to the cell surface, as a new target to develop novel antibacterials, will be reported. Future directions and perspectives will also be outlined.

Characterization of an Acinetobacter baumannii lptD Deletion Strain: Permeability Defects and Response to Inhibition of Lipopolysaccharide and Fatty Acid Biosynthesis

“…LPS is essential for the growth of most Gramnegative organisms, and the OM provides an effective permeability barrier against toxic compounds, including many antibiotics (60). Therefore, proteins involved in maintaining the permeability barrier, including those directly involved in LPS biosynthesis, may be attractive for the development of novel antibiotics for clinical use against Gram-negative pathogens alone or in combination.…”

Chemoenzymatic synthesis of ADP-d-glycero-β-d-manno-heptose and study of the substrate specificity of HldE

“…1, 2 The inhibition of the biosynthesis of these carbohydrates, or their assembly, could be exploited for novel antimicrobial drug design. 3, 4 …”

Bacterial Lipopolysaccharide

“…Several LpxC-targeting inhibitors were developed showing bactericidal activity and low toxicity in animals, but, unfortunately, resistant bacteria were also reported (Lee et al 2013). In parallel, inhibitors targeting enzymes involved in KDO biosynthesis were also explored (Cipolla et al 2011); some have potent inhibitor capabilities, but their use was restricted for several reasons such as inhibition of enzymes present in the host, reduced accessibility of the enzyme, and development of resistance. Besides this strategy, a series of hTLR4 antagonists (natural Lipid A and synthetic analogous of Lipid A with reduced numbers of acyl chains) were proposed to neutralize the effects of endotoxin by inhibiting hTLR4 signaling (Arenas 2012).…”