Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target

Abstract

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization. Over 1 million deaths per year, along with the emergence of multi- and extensively-drug resistant strains of Mtb, have triggered intensive research into the pathogenicity and biochemistry of this microorganism, guiding the development of anti-TB chemotherapeutic agents. The essential mycobacterial cell wall, sharing some common features with all bacteria, represents an apparent 'Achilles heel' that has been targeted by TB chemotherapy since the advent of TB treatment. This complex structure composed of three distinct layers, peptidoglycan, arabinogalactan and mycolic acids, is vital in supporting cell growth, virulence and providing a barrier to antibiotics. The fundamental nature of cell wall synthesis and assembly has rendered the mycobacterial cell wall as the most widely exploited target of anti-TB drugs. This review provides an overview of the biosynthesis of the prominent cell wall components, highlighting the inhibitory mechanisms of existing clinical drugs and illustrating the potential of other unexploited enzymes as future drug targets.

Keywords: antibiotics; arabinogalactan; cell wall; mycolic acids; peptidoglycan; tuberculosis.

Fig. 1.

The mycobacterial cell wall. A schematic representation of the mycobacterial cell wall, depicting the prominent features, including the glycolipids (PIMs, phosphatidyl-myo-inositol mannosides; LM, lipomannan; LAM, lipoarabinomannan; ManLAM, mannosylated lipoarabinomannan), peptidoglycan, arabinogalactan and mycolic acids. Intercalated into the mycolate layer are the acyl lipids (including TMM, trehalose monomycolate; TDM, trehalose dimycolate; DAT, diacyltrehalose; PAT, polyacyltrehalose; PDIM, phthiocerol dimycocerosate; SGL, sulfoglycolipid). The capsular material is not illustrated.

Fig. 2.

Inhibitors targeting peptidoglycan biosynthesis. The roles of the key enzymes involved in peptidoglycan biosynthesis are illustrated. Reported inhibitors are shown in red.

Fig. 3.

Inhibitors targeting arabinogalactan biosynthesis. The current understanding of the roles of enzymes involved in arabinogalactan biosynthesis. Reported inhibitors are shown in red.

Fig. 4.

Inhibitors targeting the biosynthesis of phosphatidyl-myo-inositol mannosides, lipomannan and lipoarabinomannan. The current understanding of the biosynthesis of PIMs, LM, LAM and ManLAM. Reported inhibitors are shown in red.

Fig. 5.

Inhibitors targeting mycolic acid biosynthesis. The enzymes involved in the mycolic acid biosynthetic pathway are presented. Reported inhibitors are shown in red. ‘R’ represents an acyl chain of varying carbon units in length.