The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a tenacious pathogen that has latently infected one third of the world’s population. However, conventional TB treatment regimens are no longer sufficient to tackle the growing threat of drug resistance, stimulating the development of innovative anti-tuberculosis agents, with special emphasis on new protein targets. The Mtb genome encodes ~4000 predicted proteins, among which many enzymes participate in various cellular metabolisms. For example, more than 200 proteins are involved in fatty acid biosynthesis, which assists in the construction of the cell envelope, and is closely related to the pathogenesis and resistance of mycobacteria. Here we review several essential enzymes responsible for fatty acid and nucleotide biosynthesis, cellular metabolism of lipids or amino acids, energy utilization, and metal uptake. These include InhA, MmpL3, MmaA4, PcaA, CmaA1, CmaA2, isocitrate lyases (ICLs), pantothenate synthase (PS), Lysine-ε amino transferase (LAT), LeuD, IdeR, KatG, Rv1098c, and PyrG. In addition, we summarize the role of the transcriptional regulator PhoP which may regulate the expression of more than 110 genes, and the essential biosynthesis enzyme glutamine synthetase (GlnA1). All these enzymes are either validated drug targets or promising target candidates, with drugs targeting ICLs and LAT expected to solve the problem of persistent TB infection. To better understand how anti-tuberculosis drugs act on these proteins, their structures and the structure-based drug/inhibitor designs are discussed. Overall, this investigation should provide guidance and support for current and future pharmaceutical development efforts against mycobacterial pathogenesis.

Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery

“…Mtb has four different GS genes, but only GlnA1 is essential for both in vitro and in vivo survival [ 65 ]. The main advantage of targeting GlnA1 is that its metabolites are involved in the formation of a poly- L -Glu/Gln structure, a constituent of the cell wall of mycobacteria [ 66 , 67 ]. Thus, the inhibition of this enzyme can affect both amino acid biosynthesis and the integrity of the cell wall, leading to the death of mycobacteria [ 68 , 69 , 70 ].…”

“…GlnA1 is a dodecameric enzyme, and the active site is formed by two cones connected at their narrow ends. When ATP binds to the enzyme, in the presence of two or three metal ions (Mg 2+ or Mn 2+ ), it passes from a relaxed state to a taut (active) state, also known as closed conformation [ 66 , 69 ]. In general, the mechanism allows for the entry of L -Glu and ammonium ion from one side, while ATP passes via the opposite side of the cone.…”

Serine protease Rv2569c facilitates transmission of Mycobacterium tuberculosis via disrupting the epithelial barrier by cleaving E-cadherin

“…´rin (BCG) vaccine, approximately one-third of the global population has contracted TB [4,5]. M.tb is a respiratory pathogen that primarily spreads via aerosolized droplet nuclei from person to person [6,7]. Upon inhalation of aerosol particles, bacteria often establish a stable infection in the lungs, which results in the development of the classic syndrome of pulmonary TB and transmission across the alveolar barrier to trigger systemic dissemination [8,9].…”

Advances in computational frameworks in the fight against TB: The way forward

“…Several compounds have been identified during the last few years with potential anti-tubular properties and are currently undergoing preclinical and clinical studies like, bedaquiline ( Antoci et al, 2021 ; Chakraborti et al, 2021 ; Patil & Jain, 2021 ; Deshkar & Shirure, 2022 ), PA-824 ( Lenaerts et al, 2005 ; Edwards & Field, 2022 ; Xu et al, 2022 ; Yan et al, 2022 ), and delamanid ( Skripconoka et al, 2013 ; Liu et al, 2018 ; Nasiri et al, 2022 ). Existing drugs have also been modified to repurpose them against TB and they include -riminophenazines ( Valinetz et al, 2020 ; Brunaugh et al, 2022 ), b-lactams ( Moon et al, 2018 ; Story-Roller & Lamichhane, 2018 ; Ur Rahman et al, 2018 ), and oxazolidinones ( Balasubramanian et al, 2014 ; Alghamdi et al, 2020 ; Margaryan et al, 2022 ; Ndukwe et al, 2022 ).…”