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iron metabolism in tb

Vineel P Reddy, Krishna C Chinta, Vikram Saini, Joel N Glasgow, Travis D Hull, Amie Traylor, Fernanda Rey-Stolle, Miguel P Soares, Rajhmun Madansein, Md Aejazur Rahman, Coral Barbas, Kievershen Nargan, Threnesan Naidoo, Pratistadevi K Ramdial, James F George, Anupam Agarwal, Adrie J C Steyn
Iron is an essential factor for the growth and virulence of Mycobacterium tuberculosis ( Mtb) . However, little is known about the mechanisms by which the host controls iron availability during infection. Since ferritin heavy chain (FtH) is a major intracellular source of reserve iron in the host, we hypothesized that the lack of FtH would cause dysregulated iron homeostasis to exacerbate TB disease. Therefore, we used knockout mice lacking FtH in myeloid-derived cell populations to study Mtb disease progression...
2018: Frontiers in Immunology
Manfred Nairz, Stefanie Dichtl, Andrea Schroll, David Haschka, Piotr Tymoszuk, Igor Theurl, Günter Weiss
The acute-phase response is triggered by the presence of infectious agents and danger signals which indicate hazards for the integrity of the mammalian body. One central feature of this response is the sequestration of iron into storage compartments including macrophages. This limits the availability of this essential nutrient for circulating pathogens, a host defence strategy known as 'nutritional immunity'. Iron metabolism and the immune response are intimately linked. In infections, the availability of iron affects both the efficacy of antimicrobial immune pathways and pathogen proliferation...
July 2018: Journal of Trace Elements in Medicine and Biology
Jerry Hella, Colin I Cercamondi, Francis Mhimbira, Mohamed Sasamalo, Nicole Stoffel, Marcel Zwahlen, Thomas Bodmer, Sebastien Gagneux, Klaus Reither, Michael B Zimmermann, Lorenz Risch, Lukas Fenner
BACKGROUND: Tuberculosis (TB) induces a systemic inflammatory state affecting iron homeostasis. Patients with TB often have additional comorbidities such as anemia which can result in poorer treat outcomes. We studied the contribution of anemia and the role of the iron regulatory hormone hepcidin among TB patients and household contacts. METHODS: We analyzed serum samples from 102 TB cases and 98 controls without TB, matched by age/sex, for hepcidin, iron, and inflammation parameters...
2018: PloS One
Surendra Dawadi, Helena I M Boshoff, Sae Woong Park, Dirk Schnappinger, Courtney C Aldrich
5'- O -[ N -(Salicyl)sulfamoyl]adenosine (Sal-AMS, 1 ) is a nucleoside antibiotic that inhibits incorporation of salicylate into siderophores required for bacterial iron acquisition and has potent activity against Mycobacterium tuberculosis ( Mtb ). Cinnolone analogues exemplified by 5 were designed to replace the acidic acyl-sulfamate functional group of 1 (p K a = 3) by a more stable sulfonamide linkage (p K a = 6.0) in an attempt to address potential metabolic liabilities and improve membrane permeability...
April 12, 2018: ACS Medicinal Chemistry Letters
Petra Heffeter, Veronika F S Pape, Éva A Enyedy, Bernhard K Keppler, Gergely Szakacs, Christian R Kowol
SIGNIFICANCE: During the past decades, thiosemicarbazones were clinically developed for a variety of diseases, including tuberculosis, viral infections, malaria, and cancer. With regard to malignant diseases, the class of α-N-heterocyclic thiosemicarbazones, and here especially 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), was intensively developed in multiple clinical phase I/II trials. Recent Advances: Very recently, two new derivatives, namely COTI-2 and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) have entered phase I evaluation...
February 26, 2018: Antioxidants & Redox Signaling
David L Schutzman, Erica Gatien, Samuel Ajayi, Ronald J Wong
BACKGROUND: African-American (AA) infants are known to have, overall, lower bilirubin levels than infants of other ethnicities during their birth hospitalization. However, they are known to have a higher incidence of severe hyperbilirubinemia and are over represented in the US Kernicterus Registry. Heme oxygenase-1 (HO) is the rate limiting enzyme in heme metabolism leading to the equimolar production of bilirubin, carbon monoxide (CO) and free iron (Fe). Short (S) (GT)n repeats (<25) in the promoter region of the gene encoding the inducible HO-1 isozyme augment its expression, while long (L) repeats (>33) lead to an attenuation, modulating the production of bilirubin and CO...
January 4, 2018: Journal of Perinatology: Official Journal of the California Perinatal Association
Diana A Aguilar-Ayala, Laurentijn Tilleman, Filip Van Nieuwerburgh, Dieter Deforce, Juan Carlos Palomino, Peter Vandamme, Jorge A Gonzalez-Y-Merchand, Anandi Martin
Tuberculosis (TB) is currently the number one killer among infectious diseases worldwide. Lipids are abundant molecules during the infectious cycle of Mycobacterium tuberculosis (Mtb) and studies better mimicking its actual metabolic state during pathogenesis are needed. Though most studies have focused on the mycobacterial lipid metabolism under standard culture conditions, little is known about the transcriptome of Mtb in a lipid environment. Here we determined the transcriptome of Mtb H37Rv in a lipid-rich environment (cholesterol and fatty acid) under aerobic and hypoxic conditions, using RNAseq...
December 15, 2017: Scientific Reports
Lazaro Garcia-Morales, Lizbel Leon-Solis, Irma E Monroy-Muñoz, Moises Talavera-Paulin, Jeanet Serafin-López, Iris Estrada-Garcia, Sandra Rivera-Gutierrez, Jorge F Cerna-Cortes, Addy C Helguera-Repetto, Jorge A Gonzalez-Y-Merchand
Cholesterol has been reported to play an important role during Mycobacterium tuberculosis infection and during its dormant state inside the host. We present the determination of proteomic profiles of M. tuberculosis H37Rv in the presence of cholesterol as the sole carbon source under exponential growth and in two in vitro dormancy phases (NRP1 and NRP2). Using 2D-PAGE, we detected that M. tuberculosis expressed a high diversity of proteins in both exponential and non-replicative phases. We also found that cholesterol was involved in the overexpression of some proteins related to sulfur metabolism (CysA2), electron transport (FixB), cell wall synthesis (Ald), iron storage (BfrB), protein synthesis (Tig and EF-Tu) and dormancy maintenance (HspX and TB 31...
August 4, 2017: Microbiology
Anna Johns, Daniel H Scharf, Fabio Gsaller, Hella Schmidt, Thorsten Heinekamp, Maria Straßburger, Jason D Oliver, Mike Birch, Nicola Beckmann, Katharine S Dobb, Jane Gilsenan, Bharatkumar Rash, Elaine Bignell, Axel A Brakhage, Michael J Bromley
Secondary metabolites are key mediators of virulence for many pathogens. Aspergillus fumigatus produces a vast array of these bioactive molecules, the biosynthesis of which is catalyzed by nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). Both NRPSs and PKSs harbor carrier domains that are primed for acceptance of secondary metabolic building blocks by a phosphopantetheinyl transferase (P-pant). The A. fumigatus P-pant PptA has been shown to prime the putative NRPS Pes1 in vitro and has an independent role in lysine biosynthesis; however, its role in global secondary metabolism and its impact on virulence has not been described...
July 18, 2017: MBio
Jude T Chenge, Le Van Duyet, Shalini Swami, Kirsty J McLean, Madeline E Kavanagh, Anthony G Coyne, Stephen E J Rigby, Myles R Cheesman, Hazel M Girvan, Colin W Levy, Bernd Rupp, Jens P von Kries, Chris Abell, David Leys, Andrew W Munro
The Mycobacterium tuberculosis H37Rv genome encodes 20 cytochromes P450, including P450s crucial to infection and bacterial viability. Many M. tuberculosis P450s remain uncharacterized, suggesting that their further analysis may provide new insights into M. tuberculosis metabolic processes and new targets for drug discovery. CYP126A1 is representative of a P450 family widely distributed in mycobacteria and other bacteria. Here we explore the biochemical and structural properties of CYP126A1, including its interactions with new chemical ligands...
January 27, 2017: Journal of Biological Chemistry
Kirsty J McLean, Andrew W Munro
TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb), causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and to sustain infection, with Mtb encoding large numbers of iron-binding proteins. Many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. Various heme enzymes in Mtb are validated drug targets and/or products of genes essential for bacterial viability or survival in the host...
March 2017: Drug Discovery Today
Takemasa Takii
Mycobacterium species are exposed to oxidative and nitrosylative stress from environments within and outside the host cells. After the host is infected with the bacilli, macrophages produce superoxide molecules via NADPH oxidase activity and nitric oxide (NO) via inducible NO synthase activity to kill the bacilli. The pathogenic bacilli can successfully survive in host cells via anti-oxidative and anti-nitrosylative mechanisms. In particular, Mycobacterium tuberculosis persisters pose a great problem for chemotherapy because most anti-mycobacterial drugs are ineffective against mycobacteria that are in the persistent state...
July 2015: Kekkaku: [Tuberculosis]
Selvakumar Subbian, Ruchi Pandey, Patricia Soteropoulos, G Marcela Rodriguez
Mycobacterium tuberculosis the causative agent of tuberculosis affects millions of people worldwide. New tools for treatment and prevention of tuberculosis are urgently needed. We previously showed that a ferritin (bfrB) mutant of M. tuberculosis has altered iron homeostasis and increased sensitivity to antibiotics and to microbicidal effectors produced by activated macrophages. Most importantly, M. tuberculosis lacking BfrB is strongly attenuated in mice, especially, during the chronic phase of infection. In this study, we examined whether immunization with a bfrB mutant could confer protection against subsequent infection with virulent M...
2015: Journal of Immunology Research
Krishna Kurthkoti, Priyanka Tare, Rakhi Paitchowdhury, Vykuntham Naga Gowthami, Maria J Garcia, Roberto Colangeli, Dipankar Chatterji, Valakunja Nagaraja, G Marcela Rodriguez
Emerging evidence indicates that precise regulation of iron (Fe) metabolism and maintenance of Fe homeostasis in Mycobacterium tuberculosis (Mtb) are essential for its survival and proliferation in the host. IdeR is a central transcriptional regulator of Mtb genes involved in Fe metabolism. While it is well understood how IdeR functions as a repressor, how it induces transcription of a subset of its targets is still unclear. We investigated the molecular mechanism of IdeR-mediated positive regulation of bfrB, the gene encoding the major Fe-storage protein of Mtb...
December 2015: Molecular Microbiology
Abhishek Mishra, Dhiman Sarkar
Vitamin C is a critical dietary nutrient in human which has a wide range of regulatory effects on gene expression and physiology of Mycobacterium tuberculosis that leads to a dormant drug-tolerant phenotype. In the presence of iron, vitamin C shows a high bactericidal activity even in the drug resistant phenotype of M. tuberculosis. The regulatory mechanisms underlying vitamin C induced adaptations are largely unknown due to lack of functional genomics data in this field. In this study, we attempt to characterize the direct effect of vitamin C treatment on the physiology of actively growing Mycobacterium smegmatis...
2015: Frontiers in Microbiology
Yusuke Minato, Joshua M Thiede, Shannon Lynn Kordus, Edward J McKlveen, Breanna J Turman, Anthony D Baughn
para-Aminosalicylic acid (PAS) entered clinical use in 1946 as the second exclusive drug for the treatment of tuberculosis (TB). While PAS was initially a first-line TB drug, the introduction of more potent antitubercular agents relegated PAS to the second-line tier of agents used for the treatment of drug-resistant Mycobacterium tuberculosis infections. Despite the long history of PAS usage, an understanding of the molecular and biochemical mechanisms governing the susceptibility and resistance of M. tuberculosis to this drug has lagged behind that of most other TB drugs...
September 2015: Antimicrobial Agents and Chemotherapy
Rienk A Rienksma, Maria Suarez-Diez, Hans-Joachim Mollenkopf, Gregory M Dolganov, Anca Dorhoi, Gary K Schoolnik, Vitor Ap Martins Dos Santos, Stefan He Kaufmann, Peter J Schaap, Martin Gengenbacher
BACKGROUND: The human pathogen Mycobacterium tuberculosis has the capacity to escape eradication by professional phagocytes. During infection, M. tuberculosis resists the harsh environment of phagosomes and actively manipulates macrophages and dendritic cells to ensure prolonged intracellular survival. In contrast to other intracellular pathogens, it has remained difficult to capture the transcriptome of mycobacteria during infection due to an unfavorable host-to-pathogen ratio. RESULTS: We infected the human macrophage-like cell line THP-1 with the attenuated M...
February 5, 2015: BMC Genomics
Khisimuzi Mdluli, Takushi Kaneko, Anna Upton
The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB...
January 29, 2015: Cold Spring Harbor Perspectives in Medicine
Jeffrey Green, Matthew D Rolfe, Laura J Smith
Molecular oxygen (O2) and nitric oxide (NO) are diatomic gases that play major roles in infection. The host innate immune system generates reactive oxygen species and NO as bacteriocidal agents and both require O2 for their production. Furthermore, the ability to adapt to changes in O2 availability is crucial for many bacterial pathogens, as many niches within a host are hypoxic. Pathogenic bacteria have evolved transcriptional regulatory systems that perceive these gases and respond by reprogramming gene expression...
2014: Virulence
Kip P Conner, Alex A Cruce, Matthew D Krzyaniak, Alina M Schimpf, Daniel J Frank, Paul Ortiz de Montellano, William M Atkins, Michael K Bowman
Azoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP-inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytically inert, low-spin (type II) complexes. Here, we show that the low-spin complex between a drug-metabolizing CYP2C9 variant and 4-(3-phenylpropyl)-1H-1,2,3-triazole (PPT) retains an axial water ligand despite exhibiting elements of "classic" type II optical behavior...
February 10, 2015: Biochemistry
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