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Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles' heel for the TB-causing pathogen.

ABSTRACT: Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis, remains one of the leading causes of mortality across the world. There is an urgent requirement to build a robust arsenal of effective antimicrobials, targeting novel molecular mechanisms to overcome the challenges posed by the increase of antibiotic resistance in TB. Mycobacterium tuberculosis has a unique cell envelope structure and composition, containing a peptidoglycan layer that is essential for maintaining cellular integrity and for virulence. The enzymes involved in the biosynthesis, degradation, remodelling and recycling of peptidoglycan have resurfaced as attractive targets for anti-infective drug discovery. Here, we review the importance of peptidoglycan, including the structure, function and regulation of key enzymes involved in its metabolism. We also discuss known inhibitors of ATP-dependent Mur ligases, and discuss the potential for the development of pan-enzyme inhibitors targeting multiple Mur ligases.

SUBMITTER: Maitra A

PROVIDER: S-EPMC6736417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis.

Project description:ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthetic pathway. In line with the previous findings on the regulation of mycobacterial MurD and corynebacterial MurC synthetases via phosphorylation, we found that all of the Mur synthetases interacted with the Ser/Thr protein kinases, PknA and PknB. In addition, we critically analyzed the interaction network of all of the Mur synthetases with proteins involved in cell division and cell wall PG biosynthesis to re-evaluate the importance of these key enzymes as novel therapeutic targets in anti-tubercular drug discovery.

| S-EPMC3605390 | biostudies-literature

Correction: Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis.

Project description:[This corrects the article DOI: 10.1371/journal.pone.0060143.].

| S-EPMC10965061 | biostudies-literature

Assembling of the Mycobacterium tuberculosis Cell Wall Core.

Project description:The unique cell wall of mycobacteria is essential to their viability and the target of many clinically used anti-tuberculosis drugs and inhibitors under development. Despite intensive efforts to identify the ligase(s) responsible for the covalent attachment of the two major heteropolysaccharides of the mycobacterial cell wall, arabinogalactan (AG) and peptidoglycan (PG), the enzyme or enzymes responsible have remained elusive. We here report on the identification of the two enzymes of Mycobacterium tuberculosis, CpsA1 (Rv3267) and CpsA2 (Rv3484), responsible for this function. CpsA1 and CpsA2 belong to the widespread LytR-Cps2A-Psr (LCP) family of enzymes that has been shown to catalyze a variety of glycopolymer transfer reactions in Gram-positive bacteria, including the attachment of wall teichoic acids to PG. Although individual cpsA1 and cpsA2 knock-outs of M. tuberculosis were readily obtained, the combined inactivation of both genes appears to be lethal. In the closely related microorganism Corynebacterium glutamicum, the ortholog of cpsA1 is the only gene involved in this function, and its conditional knockdown leads to dramatic changes in the cell wall composition and morphology of the bacteria due to extensive shedding of cell wall material in the culture medium as a result of defective attachment of AG to PG. This work marks an important step in our understanding of the biogenesis of the unique cell envelope of mycobacteria and opens new opportunities for drug development.

| S-EPMC5009262 | biostudies-literature

Proteomic definition of the cell wall of Mycobacterium tuberculosis.

Project description:The cell envelope of Mycobacterium tuberculosis (Mtb) is complex and diverse; composed of proteins intermingled in a matrix of peptidoglycan, mycolic acids, lipids, and carbohydrates. Proteomic studies of the Mtb cell wall have been limited; nonetheless, the characterization of resident and secreted proteins associated with the cell wall are critical to understanding bacterial survival and immune modulation in the host. In this study, the cell wall proteome was defined in order to better understand its unique biosynthetic and secretion processes. Mtb cell wall was subjected to extraction with organic solvents to remove noncovalently bound lipids and lipoglycans and remaining proteins were solubilized with either SDS, Guanidine-HCl, or TX-114. These extracts were analyzed by two-dimensional gel electrophoresis and mass-spectrometry and resulted in the identification of 234 total proteins. The lipoproteome of Mtb, enriched in the TX-114 extract, was further resolved by multidimensional chromatography and mass spectrometry to identify an additional 294 proteins. A query of the 528 total protein identifications against Neural Network or Hidden Markov model algorithms predicted secretion signals in 87 proteins. Classification of these 528 proteins also demonstrated that 35% are involved in small molecule metabolism and 25% are involved in macromolecule synthesis and degradation building upon evidence that the Mtb cell wall is actively engaged in mycobacterial survival and remodeling.

| S-EPMC2995261 | biostudies-literature

The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles' Heel of Methicillin-Resistant Staphylococcus aureus.

Project description:The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to ?-lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis. The recently published crystal structure of the complex of PBP2a with ceftaroline, a cephalosporin antibiotic that shows efficacy against MRSA, has revealed the allosteric site at 60-Å distance from the transpeptidase domain. Binding of ceftaroline to the allosteric site of PBP2a triggers conformational changes that lead to the opening of the active site from a closed conformation, where a second molecule of ceftaroline binds to give inhibition of the enzyme. The discovery of allostery in MRSA remains the only known example of such regulation of cellwall biosynthesis and represents a new paradigm in fighting MRSA. This review summarizes the present knowledge of the allosteric mechanism, the conformational changes allowing PBP2a catalysis and the means by which some clinical strains have acquired resistance to ceftaroline by disrupting the allosteric mechanism.

| S-EPMC4686279 | biostudies-literature

CAR T-Cell Therapy: Is CD28-CAR Heterodimerization Its Achilles' Heel?

Project description: Not available

| S-EPMC8635711 | biostudies-literature

Incomplete ablation of thyroid cancer: Achilles' Heel?

Project description:BackgroundIn recent years, the incidence of thyroid nodules has increased significantly. There are various ways to treat thyroid nodules, and ablation therapy is one of the important ways to treat thyroid nodules. However, there are many complications and deficiencies in the current ablation treatment of thyroid nodules, especially the incomplete ablation of thyroid cancer nodules, which limits the further application of ablation technology. In this paper, we report two cases of incomplete ablation of thyroid nodules, one of which underwent surgical treatment due to anxiety after ablation, and the postoperative pathology confirmed that there was still residual papillary thyroid carcinoma, and the other patient underwent an operation after ablation, but visited our medical institution again due to cervical lymph node metastasis in a short period of time, and after radical cervical lymph node dissection, pathology confirmed multiple cervical lymph node metastasis. Radionuclide therapy was performed after surgery, and two patients are currently receiving endocrine suppression therapy, and their condition is stable with no signs of recurrence.ConclusionThe incomplete ablation of thyroid cancer nodules limits the development of ablation therapy, making ablation treatment a double-edged sword. Guidelines and expert consensus can guide their development, but they need to evolve with the times, and a multidisciplinary diagnostic team can help screen the most suitable patients. Only by using this technology more standardly, using the most appropriate technology, and treating the most suitable patients, can benefit more and more patients.

| S-EPMC11313020 | biostudies-literature

Achilles' Heel of SARS-CoV-2 Structure.

Project description:Guided by evolutionarily signaled vulnerabilities in the structure of SARS-CoV-2, we identify epitopes in free monomers of the spike protein that steer the generation of induced or administered antibodies geared at promoting destabilization of the virus quaternary structure, thereby hampering infectivity.

| S-EPMC7552172 | biostudies-literature

Calibration: the Achilles heel of predictive analytics.

Project description:BackgroundThe assessment of calibration performance of risk prediction models based on regression or more flexible machine learning algorithms receives little attention.Main textHerein, we argue that this needs to change immediately because poorly calibrated algorithms can be misleading and potentially harmful for clinical decision-making. We summarize how to avoid poor calibration at algorithm development and how to assess calibration at algorithm validation, emphasizing balance between model complexity and the available sample size. At external validation, calibration curves require sufficiently large samples. Algorithm updating should be considered for appropriate support of clinical practice.ConclusionEfforts are required to avoid poor calibration when developing prediction models, to evaluate calibration when validating models, and to update models when indicated. The ultimate aim is to optimize the utility of predictive analytics for shared decision-making and patient counseling.

| S-EPMC6912996 | biostudies-literature

Ketogenesis: An Achilles' heel of starvation-selected persistent mycobacteria

Project description:Mycobacterial pathogens adapt to environmental stresses such as nutrient deprivation by entering a non-replicative antibiotic-tolerant state of persistence. Using a biochemically-validated data-driven approach, we identified an adaptive metabolic network underlying the mycobacterial response to starvation in M. tuberculosis, M. bovis BCG and M. smegmatis. All three species show a strong Mg+2-dependence for surviving complete nutrient deprivation, accompanied by a broad phenotypic antibiotic resistance. Multivariate analysis of RNA-seq, metabolic phenotyping and biochemical data revealed substantial metabolic remodelling involving a shift to triacylglycerol utilization with adaptation to the consequent ketoacidosis by upregulation of cytochrome P450s. Paradoxically, the ketosis-driven P450 upregulation generated substantial levels of reactive oxygen species (ROS) yet conferred hypersensitivity to killing by hydrogen peroxide-induced inactivation of the P450s that reduced ROS levels. This emergent property of starvation-induced mycobacterial persistence represents a potentially exploitable vulnerability.

2016-08-25 | GSE66883 | GEO

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