Revisiting Anti-tuberculosis Therapeutic Strategies That Target the Peptidoglycan Structure and Synthesis

Abstract

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), is one of the leading cause of death by an infectious diseases. The biosynthesis of the mycobacterial cell wall (CW) is an area of increasing research significance, as numerous antibiotics used to treat TB target biosynthesis pathways of essential CW components. The main feature of the mycobacterial cell envelope is an intricate structure, the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex responsible for its innate resistance to many commonly used antibiotics and involved in virulence. A hallmark of mAGP is its unusual peptidoglycan (PG) layer, which has subtleties that play a key role in virulence by enabling pathogenic species to survive inside the host and resist antibiotic pressure. This dynamic and essential structure is not a target of currently used therapeutics as Mtb is considered naturally resistant to most β-lactam antibiotics due to a highly active β-lactamase (BlaC) that efficiently hydrolyses many β-lactam drugs to render them ineffective. The emergence of multidrug- and extensive drug-resistant strains to the available antibiotics has become a serious health threat, places an immense burden on health care systems, and poses particular therapeutic challenges. Therefore, it is crucial to explore additional Mtb vulnerabilities that can be used to combat TB. Remodeling PG enzymes that catalyze biosynthesis and recycling of the PG are essential to the viability of Mtb and are therefore attractive targets for novel antibiotics research. This article reviews PG as an alternative antibiotic target for TB treatment, how Mtb has developed resistance to currently available antibiotics directed to PG biosynthesis, and the potential of targeting this essential structure to tackle TB by attacking alternative enzymatic activities involved in Mtb PG modifications and metabolism.

Keywords: antibiotic resistance; cell wall; mycobacteria; mycobacteriophage lysis enzymes; peptidoglycan; tuberculosis; β-lactams.

Figure 1

Summary of the mycobacterial peptidoglycan biosynthesis pathway. The peptidoglycan precursors are produced in the cytoplasm, and peptidoglycan monomeric units are assembled in the inner leaflet of the cytoplasmic membrane. Polymerization and cross-linking of tetrapeptide side chains take place at the periplasm. Inhibitors of the peptidoglycan biosynthetic enzymes are colored in red, and peptidoglycan bonds that are targeted by mycobacteriophage endolysins are colored in green. Adapted from Abrahams and Besra, 2018, with permission.

Figure 2

Schematic representation of the mycobacterial cell envelope layers. Inhibitors of mycolic acids and peptidoglycan biosynthesis are indicated in red. The mycobacteriophage lysis protein targets are indicated as follows: the pacman cartoon represents digestion of the PG by the endolysins; scissors illustrate LysB detachment of the OM. AG, arabinogalactan; CM, cytoplasmic membrane; GLP, glycolipids; LAM, lipoarabinomannan; OL, outer layer; OM, outer membrane; PG, peptidoglycan; PIMs, phosphatidylinositol mannosides; PLs, phospholipids; TDM, trehalose dimycolate. Adapted from Catalão and Pimentel, 2018 with permission from the authors.