Wall teichoic acid function, biosynthesis, and inhibition.

One of the major differences between Gram-negative and Gram-positive organisms is the presence or absence of an outer membrane (Figure 1). In Gram-negative organisms, the outer membrane protects the organism from the environment. It filters out toxic molecules and establishes a compartment, the periplasm, which retains extracytoplasmic enzymes required for cell-wall growth and degradation. It also serves as a scaffold to which proteins and polysaccharides that mediate interactions between the organism and its environment are anchored.[1] In addition, in ways that are not completely understood, the outer membrane functions along with a thin layer of peptidoglycan to help stabilize the inner membrane so that it can withstand the high osmotic pressures within the cell.[2] Figure 1 Simplified depiction of Gram-positive and Gram-negative bacterial cell envelopes. Gram-negative organisms have a distinct periplasm; Gram-positive organisms do not, but recent studies have suggested that they have a periplasmic-like compartment between ... Gram-positive organisms, in contrast, lack an outer membrane and a distinct periplasm (Figure 1). The peptidoglycan layers are consequently very thick compared to those in Gram-negative organisms.[4] These thick layers of peptidoglycan stabilize the cell membrane and also provide many sites to which other molecules can be attached. Gram-positive peptidoglycan is heavily modified with carbohydrate-based anionic polymers that play an important role in membrane integrity.[5] These anionic polymers appear to perform some of the same functions as the outer membrane: they influence membrane permeability, mediate extracellular interactions, provide additional stability to the plasma membrane, and, along with peptidoglycan, act as scaffolds for extracytoplasmic enzymes required for cell-wall growth and degradation. A major class of these cell surface glycopolymers are the teichoic acids (TAs), which are phosphate-rich molecules found in a wide range of Gram-positive bacteria, pathogens and nonpathogens alike. There are two types of TAs: the lipo-TAs (LTAs), which are anchored to the plasma membrane and extend from the cell surface into the peptidoglycan layer;[6] and the wall TAs (WTAs), which are covalently attached to peptidoglycan and extend through and beyond the cell wall (Figure 1).[7] Together, LTAs and WTAs create what has been aptly described as a “continuum of negative charge” that extends from the bacterial cell surface beyond the outermost layers of peptidoglycan.[5] Neuhaus and Baddiley comprehensively reviewed both LTAs and WTAs in 2003.[5] Since then, however, new functions for WTAs in pathogenesis have been uncovered and it has been suggested that the biosynthetic enzymes that make these polymers are targets for novel antibacterial agents.[8,9] Indeed, the first WTA-active antibiotic has just been reported.[10] This review will focus primarily on recent developments in the study of WTAs in Bacillus subtilis and Staphylococcus aureus, and will include a discussion of strategies for the discovery of WTA inhibitors and prospects for these inhibitors as antibiotics.