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.

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

“…It binds and is inhibited by β-lactams, the best known and the most important class of antibiotics in human history. There is renewed interest in PG biosynthesis as a target for anti-TB therapies as multidrug resistance becomes a serious threat (Catalao et al, 2019). In addition, GcpE/IspG (locus II) constitutes part of the methylerythritol phosphate (MEP) pathway which is considered promising targets for the development of antimycobacterial and antiparasitic agents (He et al, 2018;Wang and Dowd, 2018).…”

Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis

“…Thus, it is critical to determine which mycobacteriophages are able to infect and specifically kill drug-resistant M. tuberculosis strains. Additionally, it is critical to fully understand the mechanisms by which mycobacteriophages dismantle mycobacterial cell envelope layers in order to design new strategies using them alone, in combination, or in synergistic combination with existing drugs [ 106 , 114 ]. Indeed, studies indicate that gp39, a novel gene of mycobacteriophage SWU1 with unknown function, can disrupt mycobacterial lipid metabolism increasing the cell envelope permeability, ultimately potentiating the efficacy of multiple drugs against M. smegmatis in vitro [ 115 ].…”

Glycoconjugates, hypothetical proteins, and post‐translational modification: Importance in host–pathogen interaction and antitubercular intervention development

“…Maintaining the cell shape, mechanical resistance of the cells and withstanding hostile environments are among its many key functions (Jankute et al., 2015; Maitra et al., 2019). The unique architecture of Mtb cell envelope is comprised of high content of a variety of lipids, carbohydrates, glycoproteins, lipoproteins, proteins of unknown function, and other virulence proteins (Catalão et al., 2019; Forrellad et al., 2013). It is vital for cell growth and survival, upholding cellular integrity, and virulence (Abrahams & Besra, 2018; Catalão et al., 2019; Jankute et al., 2015; Maitra et al., 2019).…”

“…The unique architecture of Mtb cell envelope is comprised of high content of a variety of lipids, carbohydrates, glycoproteins, lipoproteins, proteins of unknown function, and other virulence proteins (Catalão et al., 2019; Forrellad et al., 2013). It is vital for cell growth and survival, upholding cellular integrity, and virulence (Abrahams & Besra, 2018; Catalão et al., 2019; Jankute et al., 2015; Maitra et al., 2019). The mycolyl–arabinogalactan–peptidoglycan (mAGP) complex and the phosphatidyl‐ myo ‐inositol‐based lipoglycans are the key features of large macro‐molecular complex of mycobacterial cell envelope synthesis and assembly.…”

“…The lipid portion is one of the main antigenic constituents triggering immune responses via immune cell pattern recognition receptors (PRRs) such as Toll‐like receptors (TLRs) and also triggers pathogen drug resistance (Angala et al., 2014; Matsunaga et al., 2004). The bacilli cell envelope complex structures are the origin of host–pathogen associations and liable to aid as a barrier against several hydrophilic antitubercular chemotherapeutics, promoting a resistance for many commonly used antibiotics (Angala et al., 2014; Catalão et al., 2019; Chiaradia et al., 2017; Jankute et al., 2015). This is due to its very low cellular permeability and the ability to accumulate mutations.…”