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.

Structural homology between 11 beta-hydroxysteroid dehydrogenase and Mycobacterium tuberculosis Inh-A enzyme: Dehydroepiandrosterone as a potential co-adjuvant treatment in diabetes-tuberculosis comorbidity

“…Among druggable targets against mycobacteria that meet the requirements for bacteria survival, the cell wall synthesis is one of the most attractive, because it contributes to support and protection ( 72 ). The Mtb cell wall is composed of three covalently linked components: long-chain mycolic acids, a cross-linked network of peptide-glycan, and highly branched arabinogalactan that establishes a promise target for the development of more effective anti-TB molecules ( 73 ). InhA is a key enzyme in the metabolism and synthesis of the Mtb cell wall and has been clinically validated by the prodrugs isoniazid (INH) and ethionamide.…”

Host- and Age-Dependent Transcriptional Changes in Mycobacterium tuberculosis Cell Envelope Biosynthesis Genes after Exposure to Human Alveolar Lining Fluid

“…These results indicate that the M.tb response to the ALF environment is not only limited to M.tb cell envelope remodeling, but also potentially affects overall M.tb metabolism and virulence [19][20][21][22][23][24][25]71], with major implications in infection progression and TB disease outcome. Since this study is only focused on the expression of cell envelope genes, ongoing global transcriptomic studies using RNA-seq technologies will provide clues as to which other metabolic pathways are altered by the human ALF environment, with the potential to decipher key upregulated bacterial determinants during early stages of infection that can be targeted for the development of new preventative and therapeutic strategies [72]. Indeed, M.tb is exposed to ALF during the first infection stages upon deposition to the alveolar space, which is studied here, but also when escaping from necrotic cells or in cavities during active TB episodes leading to transmission [17].…”

Host- and age-dependent transcriptional changes in Mycobacterium tuberculosis cell envelope biosynthesis genes after exposure to human alveolar lining fluid

“…These results indicate that the M.tb response to the ALF environment is not only limited to M.tb cell envelope remodeling, but also potentially affects overall M.tb metabolism and virulence [19][20][21][22][23][24][25]27], with major implications in infection progression and TB disease outcome. Further global transcriptomic studies will be able to provide clues as to which other metabolic pathways are altered by the human ALF environment, with the potential to decipher key upregulated bacterial determinants during early stages of infection that can be targeted for the development of new preventative and therapeutic strategies [74]. Indeed, M.tb is exposed to ALF during the first infection stages upon deposition to the alveolar space, but also when escaping from necrotic cells or in cavities during active TB episodes leading to transmission [17].…”