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Nature Microbiology Oct 2023The order Corynebacteriales includes major industrial and pathogenic Actinobacteria such as Corynebacterium glutamicum or Mycobacterium tuberculosis. These bacteria have...
The order Corynebacteriales includes major industrial and pathogenic Actinobacteria such as Corynebacterium glutamicum or Mycobacterium tuberculosis. These bacteria have multi-layered cell walls composed of the mycolyl-arabinogalactan-peptidoglycan complex and a polar growth mode, thus requiring tight coordination between the septal divisome, organized around the tubulin-like protein FtsZ, and the polar elongasome, assembled around the coiled-coil protein Wag31. Here, using C. glutamicum, we report the discovery of two divisome members: a gephyrin-like repurposed molybdotransferase (Glp) and its membrane receptor (GlpR). Our results show how cell cycle progression requires interplay between Glp/GlpR, FtsZ and Wag31, showcasing a crucial crosstalk between the divisome and elongasome machineries that might be targeted for anti-mycobacterial drug discovery. Further, our work reveals that Corynebacteriales have evolved a protein scaffold to control cell division and morphogenesis, similar to the gephyrin/GlyR system that mediates synaptic signalling in higher eukaryotes through network organization of membrane receptors and the microtubule cytoskeleton.
Topics: Eukaryota; Bacterial Proteins; Cell Division; Mycobacterium tuberculosis
PubMed: 37679597
DOI: 10.1038/s41564-023-01473-0 -
Journal of Medical Microbiology Nov 2023Tubercidin is an adenosine analogue that has been shown to exhibit good activity against some tumours and parasites. In this study, the activity of tubercidin was...
Tubercidin is an adenosine analogue that has been shown to exhibit good activity against some tumours and parasites. In this study, the activity of tubercidin was evaluated against (Mtb) and nontuberculosis Mycobacteria (NTM). For determining the MICs of tubercidin, 23 fully drug-sensitive (DS) Mtb strains, 33 multi-drug resistance tuberculosis (MDR-TB) strains, 29 pre-extensively drug-resistant tuberculosis (pre-XDR-TB) strains, 21 extensively drug-resistant tuberculosis (XDR-TB) strains, 17 rapidly growing mycobacteria (RGM) and nine slowly growing mycobacteria (SGM) references strains were tested by microplate-based Alamar Blue assay (MABA) method. The results indicate that tubercidin has high activity against some drug-resistance Mtb strains and NTM reference strains, which warrants further investigation on the actions of tubercidin and its derivatives as potential drugs for mycobacterial infections.
Topics: Humans; Mycobacterium tuberculosis; Tubercidin; Extensively Drug-Resistant Tuberculosis; Nontuberculous Mycobacteria; Mycobacterium Infections
PubMed: 37910006
DOI: 10.1099/jmm.0.001763 -
Nature Communications Sep 2023Tuberculosis continues to pose a serious threat to global health. Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen that...
Tuberculosis continues to pose a serious threat to global health. Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen that relies on various mechanisms to survive and persist within the host. Among their many virulence factors, mycobacteria encode Mce systems. Some of these systems are implicated in lipid uptake, but the molecular basis for Mce function(s) is poorly understood. To gain insights into the composition and architecture of Mce systems, we characterized the putative Mce1 complex involved in fatty acid transport. We show that the Mce1 system in Mycobacterium smegmatis comprises a canonical ATP-binding cassette transporter associated with distinct heterohexameric assemblies of substrate-binding proteins. Furthermore, we establish that the conserved membrane protein Mce1N negatively regulates Mce1 function via a unique mechanism involving blocking transporter assembly. Our work offers a molecular understanding of Mce complexes, sheds light on mycobacterial lipid metabolism and its regulation, and informs future anti-mycobacterial strategies.
Topics: Membrane Proteins; Mycobacterium smegmatis; Mycobacterium tuberculosis; Membrane Transport Proteins; ATP-Binding Cassette Transporters
PubMed: 37736771
DOI: 10.1038/s41467-023-41578-y -
Journal of Immunology (Baltimore, Md. :... Aug 2023Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While...
Retinoic acid (RA) is a fundamental vitamin A metabolite involved in regulating immune responses through the nuclear RA receptor (RAR) and retinoid X receptor. While performing experiments using THP-1 cells as a model for Mycobacterium tuberculosis infection, we observed that serum-supplemented cultures displayed high levels of baseline RAR activation in the presence of live, but not heat-killed, bacteria, suggesting that M. tuberculosis robustly induces the endogenous RAR pathway. Using in vitro and in vivo models, we have further explored the role of endogenous RAR activity in M. tuberculosis infection through pharmacological inhibition of RARs. We found that M. tuberculosis induces classical RA response element genes such as CD38 and DHRS3 in both THP-1 cells and human primary CD14+ monocytes via a RAR-dependent pathway. M. tuberculosis-stimulated RAR activation was observed with conditioned media and required nonproteinaceous factor(s) present in FBS. Importantly, RAR blockade by (4-[(E)-2-[5,5-dimethyl-8-(2-phenylethynyl)-6H-naphthalen-2-yl]ethenyl]benzoic acid), a specific pan-RAR inverse agonist, in a low-dose murine model of tuberculosis significantly reduced SIGLEC-F+CD64+CD11c+high alveolar macrophages in the lungs, which correlated with 2× reduction in tissue mycobacterial burden. These results suggest that the endogenous RAR activation axis contributes to M. tuberculosis infection both in vitro and in vivo and reveal an opportunity for further investigation of new antituberculosis therapies.
Topics: Mice; Humans; Animals; Receptors, Retinoic Acid; Mycobacterium tuberculosis; Drug Inverse Agonism; Tretinoin; Retinoid X Receptors
PubMed: 37395686
DOI: 10.4049/jimmunol.2200555 -
Current Opinion in Microbiology Jun 2024Members of the order Mycobacteriales are distinguished by a characteristic diderm cell envelope, setting them apart from other Actinobacteria species. In addition to the... (Review)
Review
Members of the order Mycobacteriales are distinguished by a characteristic diderm cell envelope, setting them apart from other Actinobacteria species. In addition to the conventional peptidoglycan cell wall, these organisms feature an extra polysaccharide polymer composed of arabinose and galactose, termed arabinogalactan. The nonreducing ends of arabinose are covalently linked to mycolic acids (MAs), forming the immobile inner leaflet of the highly hydrophobic MA membrane. The contiguous outer leaflet of the MA membrane comprises trehalose mycolates and various lipid species. Similar to all actinobacteria, Mycobacteriales exhibit apical growth, facilitated by a polar localized elongasome complex. A septal cell envelope synthesis machinery, the divisome, builds instead of the cell wall structures during cytokinesis. In recent years, a growing body of knowledge has emerged regarding the cell wall synthesizing complexes of Mycobacteriales., focusing particularly on three model species: Corynebacterium glutamicum, Mycobacterium smegmatis, and Mycobacterium tuberculosis.
Topics: Cell Wall; Mycolic Acids; Galactans; Peptidoglycan; Mycobacterium tuberculosis; Corynebacterium glutamicum; Mycobacterium smegmatis; Arabinose; Bacterial Proteins
PubMed: 38653035
DOI: 10.1016/j.mib.2024.102478 -
Frontiers in Cellular and Infection... 2023
Topics: MicroRNAs; Exosomes; Mycobacterium tuberculosis; Biomarkers; Gene Expression Profiling
PubMed: 37565065
DOI: 10.3389/fcimb.2023.1239739 -
Tuberculosis (Edinburgh, Scotland) Dec 2023The date of Mycobacterium tuberculosis complex emergence has been the subject of long debates. New studies joining archaeological efforts with sequencing methods raise... (Review)
Review
The date of Mycobacterium tuberculosis complex emergence has been the subject of long debates. New studies joining archaeological efforts with sequencing methods raise high hopes for solving whether this emergence is closer to 70,000 or to 6000 years before present. Inferring the date of emergence of this pathogen based on sequence data requires a molecular clock. Several clocks inferred from different types of loci and/or different samples, using both sound reasoning and reliable data, are actually very different, which we refer to as the paradoxes of M. tuberculosis molecular evolution. After having presented these paradoxes, we will remind the limits of the molecular clocks used in the different studies such as the assumption of homogeneous substitution rate. We will then review recent results that shed new light on the characteristics of M. tuberculosis molecular evolution: traces of diverse selection pressures, the impact of host dynamics, etc. We provide some ideas on what to do next to get nearer to a reliable dating of Mycobacterium tuberculosis complex emergence. Among them, the collection of additional remains from ancient tuberculosis seems still essential.
Topics: Humans; Mycobacterium tuberculosis; Tuberculosis; Evolution, Molecular
PubMed: 38012921
DOI: 10.1016/j.tube.2023.102378 -
Molecules (Basel, Switzerland) Apr 2024Targeting translation factor proteins holds promise for developing innovative anti-tuberculosis drugs. During protein translation, many factors cause ribosomes to stall... (Review)
Review
Targeting translation factor proteins holds promise for developing innovative anti-tuberculosis drugs. During protein translation, many factors cause ribosomes to stall at messenger RNA (mRNA). To maintain protein homeostasis, bacteria have evolved various ribosome rescue mechanisms, including the predominant trans-translation process, to release stalled ribosomes and remove aberrant mRNAs. The rescue systems require the participation of translation elongation factor proteins (EFs) and are essential for bacterial physiology and reproduction. However, they disappear during eukaryotic evolution, which makes the essential proteins and translation elongation factors promising antimicrobial drug targets. Here, we review the structural and molecular mechanisms of the translation elongation factors EF-Tu, EF-Ts, and EF-G, which play essential roles in the normal translation and ribosome rescue mechanisms of (Mtb). We also briefly describe the structure-based, computer-assisted study of anti-tuberculosis drugs.
Topics: Mycobacterium tuberculosis; Bacterial Proteins; Protein Biosynthesis; Peptide Elongation Factors; Antitubercular Agents; Ribosomes; Models, Molecular; Tuberculosis; Protein Conformation
PubMed: 38731549
DOI: 10.3390/molecules29092058 -
Trends in Microbiology Mar 2024The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular... (Review)
Review
The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular compartments. Therefore, TB chemotherapy requires antibiotics crossing multiple biological membranes to reach distinct subcellular compartments and target these bacterial populations. These compartments are also dynamic, and our understanding of intracellular pharmacokinetics (PK) often represents a challenge for antitubercular drug development. In recent years, the development of high-resolution imaging approaches in the context of host-pathogen interactions has revealed the intracellular distribution of antibiotics at a new level, yielding discoveries with important clinical implications. In this review, we describe the current knowledge regarding cellular PK of antibiotics and the complexity of drug distribution within the context of TB. We also discuss the recent advances in quantitative imaging and highlight their applications for drug development in the context of how intracellular environments and microbial localisation affect TB treatment efficacy.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Host-Pathogen Interactions; Treatment Outcome
PubMed: 37709598
DOI: 10.1016/j.tim.2023.08.009 -
Microbiology and Immunology Aug 2023Tobacco consumption increases the susceptibility to develop infectious diseases such as tuberculosis (TB). Nicotine (Nc) is the main component of cigarette smoke with...
Tobacco consumption increases the susceptibility to develop infectious diseases such as tuberculosis (TB). Nicotine (Nc) is the main component of cigarette smoke with immunomodulatory properties, however, its effect on Mycobacterium tuberculosis (Mtb) has been scarcely investigated. The present study evaluated the effect of nicotine on the growth of Mtb and on the induction of virulence-related genes. Mycobacteria were exposed to different concentrations of nicotine then Mtb growth was evaluated. Subsequently, the expression of the virulence-related genes lysX, pirG, fad26, fbpa, ompa, hbhA, esxA, esxB, hspx, katG, lpqh, and caeA was evaluated by RT-qPCR. The effect of nicotine on intracellular Mtb was also evaluated. The results showed that nicotine promotes the growth of Mtb both extracellularly and intracellularly and increases the expression of genes related to virulence. In summary, nicotine promotes the growth of Mtb and the expression of virulence-related genes that could be correlated with the increased the risk of smokers developing TB.
Topics: Humans; Mycobacterium tuberculosis; Virulence; Nicotine; Tuberculosis; Virulence Factors
PubMed: 37380811
DOI: 10.1111/1348-0421.13085