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Jyothi Padiadpu, Priyanka Baloni, Kushi Anand, MohamedHusen Munshi, Chandrani Thakur, Abhilash Mohan, Amit Singh, Nagasuma Chandra
The global mechanisms and associated molecular alterations that occur in drug-resistant mycobacteria are poorly understood. To address this, we obtain genomics data and then construct a genome-scale response network in isoniazid-resistant Mycobacterium smegmatis and apply a network-mining algorithm. Through this, we decipher global alterations in an unbiased manner and identify emergent vulnerabilities in resistant bacilli, of which redox response was prominent. Using phenotypic profiling, we find that resistant bacilli exhibit collateral sensitivity to several compounds that block antioxidant responses...
September 9, 2016: ACS Infectious Diseases
Pooja Gopal, Michelle Yee, Jickky Sarathy, Jian Liang Low, Jansy P Sarathy, Firat Kaya, Véronique Dartois, Martin Gengenbacher, Thomas Dick
Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM)...
September 9, 2016: ACS Infectious Diseases
Fatemeh Nooshabadi, Hee-Jeong Yang, Yunfeng Cheng, Madeleine S Durkee, Hexin Xie, Jianghong Rao, Jeffrey D Cirillo, Kristen C Maitland
Tuberculosis is a pulmonary disease with an especially high mortality rate in immuno-compromised populations, specifically children and HIV positive individuals. The causative agent, Mycobacterium tuberculosis (Mtb), is a very slow growing and difficult organism to work with, making both diagnosis and development of effective treatments cumbersome. We utilize a fiber-optic fluorescence microendoscope integrated with a whole-body imaging system for in vivo Mtb detection. The system exploits an endogenous enzyme of Mtb (β-lactamase, or BlaC) using a BlaC-specific NIR fluorogenic substrate...
October 18, 2016: Journal of Biophotonics
P Mencarini, R Bellagamba, A Oliva, P Ghirga, M L Giancola, A Corpolongo, T Ascoli Bartoli, P De Nardo, A Baiocchini, F Del Nonno, P Narciso, E Nicastri
The diagnosis of sarcoidosis in a patient living with HIV infection is an uncommon event and a challenge for clinicians. Clinical manifestations are variable and fluctuating depending to adherence to ARV therapy and to the level of CD4 count. We analyze here one chronic case in which sarcoidosis appeared clinically two years after pulmonary tuberculosis. The course of the disease was influenced and prolonged by frequent interruptions of antiretroviral therapy. Moreover the diagnosis and the decision to treat have been delayed by the need of exclusion of other pathologies, principally tuberculosis reactivation/reinfection, other mycobacterial diseases, hematologic malignancies...
2016: Respiratory Medicine Case Reports
Himanshu Pandey, Sarita Tripathi, Kanchan Srivastava, Dinesh K Tripathi, Mrigank Srivastava, Surya Kant, Kishore K Srivastava, Ashish Arora
BACKGROUND: We have characterized two immunogenic proteins, Rv1197 and Rv1198, of the Esx-5 system of the ESAT-6 family of Mycobacterium tuberculosis H37Rv. METHODS: The complex formation between Rv1197 and Rv1198 was characterized by biophysical techniques. The reactivity of serum from TB patients towards these proteins was characterized by ELISA. Lymphocyte proliferation and cytokine induction were followed in restimulated splenocytes from immunized mice by using MTT assay and CBA flowcytometry, respectively...
October 14, 2016: Biochimica et Biophysica Acta
Aníbal M Reyes, Diego S Vazquez, Ari Zeida, Martín Hugo, M Dolores Piñeyro, María Inés De Armas, Darío Estrin, Rafael Radi, Javier Santos, Madia Trujillo
Mycobacterium tuberculosis (M. tuberculosis) is the intracellular bacterium responsible for tuberculosis disease (TD). Inside the phagosomes of activated macrophages, M. tuberculosis is exposed to cytotoxic hydroperoxides such as hydrogen peroxide, fatty acid hydroperoxides and peroxynitrite. Thus, the characterization of the bacterial antioxidant systems could facilitate novel drug developments. In this work, we characterized the product of the gene Rv1608c from M. tuberculosis, which according to sequence homology had been annotated as a putative peroxiredoxin of the peroxiredoxin Q subfamily (PrxQ B from M...
October 14, 2016: Free Radical Biology & Medicine
Simon Mutembo, Jane N Mutanga, Kebby Musokotwane, Lutangu Alisheke, Christopher C Whalen
BACKGROUND: Co-infection with Mycobacterium tuberculosis remains a leading cause of morbidity and mortality among HIV infected individuals especially in developing countries. Early initiation of cART in these patients when CD4+ T cell count is less than 200cells/mm(3) has reduced disease progression and mortality. However for patients with higher CD4+ T cell counts greater than 350cells/mm(3) evidence is conflicting. In this study we seek to evaluate the effectiveness of cART in reducing mortality among TB-HIV co-infected patients with CD4 + T cells above 350cells/mm(3) at the time of TB diagnosis...
October 17, 2016: BMC Infectious Diseases
Diego G Ghiano, Agustina de la Iglesia, Nina Liu, Peter J Tonge, Héctor R Morbidoni, Guillermo R Labadie
A collection of 1,2,3-triazoles unsaturated fatty acid mimics were efficiently synthesized by click chemistry. The 1,4-disubstituted analogs prepared covered different alkyl chain lengths and triazole positions. The compounds were subsequently tested against Mycobacterium tuberculosis, being most of them active with some of the analogs displaying activity at micromolar concentration. The most potent member of the series has the triazole moiety on the C-2 position with a carbon chain of eight or ten carbon atoms...
September 28, 2016: European Journal of Medicinal Chemistry
Anand Babu Velappan, Mamilla R Charan Raja, Dhrubajyoti Datta, Yi Ting Tsai, Iman Halloum, Baojie Wan, Laurent Kremer, Hugo Gramajo, Scott G Franzblau, Santanu Kar Mahapatra, Joy Debnath
Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc(2)6030 strains. The best molecule with a methyl at ortho position of the first aromatic ring and prenyl group at the meta position of the second aromatic ring showed the MIC value of 5...
September 26, 2016: European Journal of Medicinal Chemistry
Shradha Subedi, Fanrong Kong, Peter Jelfs, Timothy J Gray, Meng Xiao, Vitali Sintchenko, Sharon C-A Chen
Accurate identification of slowly growing nontuberculous mycobacteria (SG-NTM) of clinical significance remains problematic. This study evaluated a novel method of SG-NTM identification by amplification of the mycobacterial 16S-23S rRNA internal transcribed spacer (ITS) region followed by resolution of amplified fragments by sequencer-based capillary gel electrophoresis (SCGE). Fourteen American Type Culture Collection (ATCC) strains and 103 clinical/environmental isolates (total n = 24 species) of SG-NTM were included...
2016: PloS One
Kenneth N Olivier, David E Griffith, Gina Eagle, John P McGinnis Ii, Liza Micioni, Keith Liu, Charles L Daley, Kevin L Winthrop, Stephen Ruoss, Doreen J Addrizzo-Harris, Patrick A Flume, Daniel Dorgan, Matthias Salathe, Barbara A Brown-Elliott, Renu Gupta, Richard J Wallace
Rationale Lengthy multi-drug, toxic, and low efficacy regimens limit management of pulmonary nontuberculous mycobacterial (PNTM) disease. Objective This phase 2 study investigated efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory PNTM (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multi-drug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days...
October 17, 2016: American Journal of Respiratory and Critical Care Medicine
Liqin Wang, Miao Xu, Noel Southall, Wei Zheng, Shuishu Wang
Tuberculosis (TB) still kills over 1.5 million people per year despite available anti-TB drugs. The emergence of drug-resistant TB poses a major threat to public health and prompts for an urgent need for new and more effective drugs. The long duration needed to treat TB by the current TB drugs, which target the essential cellular activities, inevitably leads to the emergence of drug-resistance. PhoP of Mycobacterium tuberculosis (MTB), an essential virulence factor, is a novel target for drug development. Guided by the crystal structure of the PhoP-DNA complex, we designed and developed a robust high-throughput screening assay for identification of PhoP inhibitors that disrupt the PhoP-DNA binding...
October 10, 2016: Combinatorial Chemistry & High Throughput Screening
D Kušar, U Zajc, V Jenčič, M Ocepek, J Higgins, M Žolnir-Dovč, M Pate
Fish are commonly infected with non-tuberculous mycobacteria (NTM), which should be regarded as potential pathogens when handling aquarium fish and equipment. This study examined 107 aquarium fish from pet shops. Cultivation of the fish samples using different selective media was conducted for identification of NTM. Isolates were identified using the GenoType Mycobacterium common mycobacteria and additional species assays, sequencing of the 16S rRNA and rpoB genes, and real-time PCR assay for identification of Mycobacterium (M...
October 17, 2016: Journal of Fish Diseases
Mark L Metersky, Antranik Mangardich
Chronic suppurative lung disease (CSLD), characterized by a bronchiectasis-like syndrome in the absence of bronchial dilatation, is well described in the pediatric literature. In some patients, it may be a precursor of bronchiectasis. In adults, this syndrome has not been well described. We present four adult patients without obvious causative exposures who presented with prolonged cough and purulent sputum. Sputum cultures revealed a variety of Gram negative bacteria, fungi and mycobacteria. High resolution CT scanning did not reveal bronchiectasis...
September 2016: Journal of Thoracic Disease
Carlos Wong-Baeza, Albany Reséndiz-Mora, Luis Donis-Maturano, Isabel Wong-Baeza, Luz Zárate-Neira, Juan Carlos Yam-Puc, Juana Calderón-Amador, Yolanda Medina, Carlos Wong, Isabel Baeza, Leopoldo Flores-Romo
Anti-lipid IgG antibodies are produced in some mycobacterial infections and in certain autoimmune diseases [such as anti-phospholipid syndrome, systemic lupus erythematosus (SLE)]. However, few studies have addressed the B cell responses underlying the production of these immunoglobulins. Anti-lipid IgG antibodies are consistently found in a murine model resembling human lupus induced by chlorpromazine-stabilized non-bilayer phospholipid arrangements (NPA). NPA are transitory lipid associations found in the membranes of most cells; when NPA are stabilized they can become immunogenic and induce specific IgG antibodies, which appear to be involved in the development of the mouse model of lupus...
2016: Frontiers in Immunology
Hiroshi Ikeda, Kiwamu Nakamura, Mei Ikenori, Takahiro Saito, Keisuke Nagamine, Minoru Inoue, Takuro Sakagami, Hiroko Suzuki, Mariko Usui, Keiji Kanemitsu, Akinori Matsumoto, Takuro Shinbo
We herein report a case of disseminated Mycobacterium avium infection that involved both optic nerves, the conjunctiva, the right lower lung, and multiple skin lesions, including a thoracic nodule. The patient was a 65-year-old man without any significant medical history. The pathogen was detected in the patient's eye discharge, sputum, bronchial lavage fluid, and thoracic nodule. Anti-mycobacterial chemotherapy, including clarithromycin, rifampicin, and ethambutol, was administered, and the thoracic nodule was resected...
2016: Internal Medicine
Laura Pérez-Lago, Santiago Izco, Marta Herranz, Griselda Tudó, María Carcelén, Iñaki Comas, Olalla Sierra, Juliá González, María Jesús Ruiz-Serrano, Juan Eyene, Emilio Bouza, Darío García-de-Viedma
OBJECTIVE: Molecular epidemiology techniques in tuberculosis (TB) can identify high-risk strains that are actively transmitted. We aimed to implement a novel strategy to optimize the identification and control of MDR-TB in a specific population. METHODS: We developed a strain-specific-PCR tailored from whole-genome-sequencing (WGS) data to track a specific multidrug-resistant prevalent strain in Equatorial Guinea (EG-MDR). RESULTS: The PCR was applied prospectively on remnants of GeneXpert reaction mixtures owing to the lack of culture facilities in EG...
October 13, 2016: Clinical Microbiology and Infection
Guislaine Refregier, Edgar Abadia, Tomoshige Matsumoto, Hiromi Ano, Tetsuya Takashima, Izuo Tsuyuguchi, Elif Aktas, Füsun Cömert, Michel Kireopori Gomgnimbou, Stefan Panaiotov, Jody Phelan, Francesc Coll, Ruth Mcnerney, Arnab Pain, Taane G Clark, Christophe Sola
Two geographically distant M. tuberculosis sublineages, Tur from Turkey and T3-Osaka from Japan, exhibit partially identical genotypic signatures (identical 12-loci MIRU-VNTR profiles, distinct spoligotyping patterns). We investigated T3-Osaka and Tur sublineages characteristics and potential genetic relatedness, first using MIRU-VNTR locus analysis on 21 and 25 samples of each sublineage respectively, and second comparing Whole Genome Sequences of 8 new samples to public data from 45 samples uncovering human tuberculosis diversity...
October 13, 2016: Infection, Genetics and Evolution
Susmita K Singh, Anna-Maria Andersson, Rada Ellegård, Cecilia S Lindestam Arlehamn, Alessandro Sette, Marie Larsson, Olle Stendahl, Robert Blomgran
HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC)-mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB...
October 13, 2016: American Journal of Pathology
Marie-Odile Husson, Delphine Ley, Céline Portal, Madeleine Gottrand, Thomas Hueso, Jean-Luc Desseyn, Frédéric Gottrand
OBJECTIVES: Although n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) are used widely in the treatment of chronic inflammatory diseases, their effect in infectious disease requires a particular attention. METHODS: The present article discusses their anti-inflammatory and immune properties involved in the host defence and presents a systematic review of the effects of their oral administration on the prevention and outcome of experimental and clinical infections...
October 13, 2016: Journal of Infection
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