Hit 'em Where It Hurts: Gram-Negative Bacterial Lipopolysaccharide as a Vaccine Target

Abstract

Infections with antimicrobial-resistant (AMR) bacteria pose an increasing threat to the ability to perform surgical procedures, organ transplantation, and treat cancer among many other medical conditions. There are few new antimicrobials in the development pipeline. Vaccines against AMR Gram-negative bacteria may reduce the use of antimicrobials and prevent bacterial transmission. This review traces the origins of lipopolysaccharide (LPS)-based vaccines against Gram-negative bacteria, the role of O polysaccharides and LPS core regions as potential vaccine targets, the development of new vaccine technologies, and their application to vaccines in current development.

Keywords: Gram-negative bacteria; O polysaccharide; antimicrobial resistance; endotoxin; lipopolysaccharide; vaccine.

FIG 1

Fine structure of lipopolysaccharide (LPS). (A) Gram-negative bacterial cell envelope with LPS embedded in the outer membrane. (B) Details of three main components of LPS: O-specific chains (OPS); core region (including inner and outer regions); lipid A. Bacteria expressing all 3 regions are termed as having a “smooth” (S) LPS, while those that express core and lipid A, but lack the OPS are termed as having “rough” (R) LPS. The OPS is composed of unique repeat units of sugars that confer serologic specificity to each GNB. The core region is comprised of sugars that are highly conserved among Enterobacteriaceae, with the inner core more conserved than the outer core. The different core chemotypes (Ra through Re) result from enzymatic defects during the biosynthesis of the core, such that a lack in any one biosynthetic enzyme results in an inability to add that distal sugars to the elongating core (see reference for details). The lipid A structure varies among Gram-negative bacteria. Variation in both the number and length of fatty acids as well as in the phosphorylation of lipid A impacts its endotoxic activity. GlcNAc, N-acetylglucosamine; GlcN, glucosamine; Glu, glucose; Gal, galactose; Hep, heptose; Kdo, 2-keto-3-deoxyoctonate; P, phosphate; Etn, ethanolamine. Vaccine considerations: O polysaccharide-specific vaccines conjugate either the OPS or the core + OPS (C-OPS) to a protein carrier. The E. coli O111:B4, J5 mutant is a Rc chemotype core vaccine, while the S. minnesota Re595 vaccine is a Re mutant. The WNI-225 MAb targets an epitope in the Rc core. An LPS vaccine may be “detoxified” by mild acid hydrolysis that releases the lipid A (red line), by modification of the fatty acids by mild base treatment (blue outline), or by removing a phosphate from the distal GlcN bearing two fatty acids (though the latter is not done commercially).