Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains the leading cause of death from an infectious bacterium and is responsible for 1.8 million deaths annually. The emergence of drug resistance, together with the need for a shorter more effective regimen, has prompted the drive to identify novel therapeutics with the bacterial cell surface emerging as a tractable area for drug development. Mtb assembles a unique, waxy, and complex cell envelope comprised of the mycolyl-arabinogalactan-peptidoglycan complex and an outer capsule like layer, which are collectively essential for growth and pathogenicity while serving as an inherent barrier against antibiotics. A detailed understanding of the biosynthetic pathways required to assemble the polymers that comprise the cell surface will enable the identification of novel drug targets as these structures provide a diversity of biochemical reactions that can be targeted. Herein, we provide an overview of recently described mycobacterial cell wall targeting compounds, novel drug combinations and their modes of action. We anticipate that this summary will enable prioritization of the best pathways to target and triage of the most promising molecules to progress for clinical assessment.

Keywords: arabinogalactan; cell surface; mycolic acids; peptidoglycan; tuberculosis drugs.

Figure 1

Mycobacterial cell wall and its validated and potential drug targets. Shown are the cytoplasmic and periplasmic biosynthetic pathways for the different polymers in the mycobacterial cell wall (peptidoglycan, arabinogalactan, mycolic acids, and glycolipids). Cytoplasmic and periplasmic enzymes already validated as drug targets and potential drug targets are shown in red text. Membrane channels involved in PG recycling, GlcNAc-1-P-L-rha-Galf30-, DPA-, Ac1/Ac2PIM4-, and surface glycolipid translocation remain to be identified (depicted by “?”).