Abstract
Bacterial antibiotic resistance is a rapidly expanding problem in the world today. Functionalization of the outer membrane of Gram-negative bacteria provides protection from extracellular antimicrobials, and serves as an innate resistance mechanism. Lipopolysaccharides (LPS) are a major cell-surface component of Gram-negative bacteria that contribute to protecting the bacterium from extracellular threats. LPS is biosynthesized by the sequential addition of sugar moieties by a number of glycosyltransferases (GTs). Heptosyltransferases catalyze the addition of multiple heptose sugars to form the core region of LPS; there are at most four heptosyltransferases found in all Gram-negative bacteria. The most studied of the four is HepI. Cells deficient in HepI display a truncated LPS on their cell surface, causing them to be more susceptible to hydrophobic antibiotics. HepI–IV are all structurally similar members of the GT-B structural family, a class of enzymes that have been found to be highly dynamic. Understanding conformational changes of heptosyltransferases are important to efficiently inhibiting them, but also contributing to the understanding of all GT-B enzymes. Finding new and smarter methods to inhibit bacterial growth is crucial, and the Heptosyltransferases may provide an important model for how to inhibit many GT-B enzymes.
Highlights
Well before the discovery of penicillin, bacteria have been evolving to resist natural antibiotics and other extracellular threats [1]; advances in medical techniques and over use of antibiotics has lead to an exponential increase in resistance
The LPS is composed of three main sections: a hydrophobic lipid A anchored to the membrane, a core oligosaccharide containing octulose and heptose sugar moieties, and a repeating O-antigen region containing a diversity of sugars that are unique to bacterial cell surfaces [11,12,13]; these components vary slightly between different bacteria [9,14]
A computational model of E. coli HepIV was created using the I-Tasser protein structure prediction program and it appears similar to heptosyltransferase I (HepI) and HepII crystal structure [52,53,54]
Summary
Well before the discovery of penicillin, bacteria have been evolving to resist natural antibiotics and other extracellular threats [1]; advances in medical techniques and over use of antibiotics has lead to an exponential increase in resistance. LPS are the primary component of the OM in most species of Gram-negative bacteria and have been shown to play an important role in cell motility, intestinal colonization, bacterial biofilm formation, and antibiotic resistance [8,9]. The LPS is composed of three main sections: a hydrophobic lipid A anchored to the membrane, a core oligosaccharide containing octulose and heptose sugar moieties, and a repeating O-antigen region containing a diversity of sugars that are unique to bacterial cell surfaces (including pentoses, deoxy-hexoses, lactyl functionalized hexoses, heptoses and nonuloses) [11,12,13]; these components vary slightly between different bacteria [9,14]. Truncation of the LPS by mutations to the inner core display a deep-rough phenotype and exhibit hypersensitivity to hydrophobic antibiotics and detergents [4,20,21]
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