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Tuberculosis, antimicrobial drug resistance

Joshua M Thiede, Shannon L Kordus, Breanna J Turman, Joseph A Buonomo, Courtney C Aldrich, Yusuke Minato, Anthony D Baughn
The ability to revitalize and re-purpose existing drugs offers a powerful approach for novel treatment options against Mycobacterium tuberculosis and other infectious agents. Antifolates are an underutilized drug class in tuberculosis (TB) therapy, capable of disrupting the biosynthesis of tetrahydrofolate, an essential cellular cofactor. Based on the observation that exogenously supplied p-aminobenzoic acid (PABA) can antagonize the action of antifolates that interact with dihydropteroate synthase (DHPS), such as sulfonamides and p-aminosalicylic acid (PAS), we hypothesized that bacterial PABA biosynthesis contributes to intrinsic antifolate resistance...
December 1, 2016: Scientific Reports
Valakunja Nagaraja, Adwait A Godbole, Sara R Henderson, Anthony Maxwell
Tuberculosis (TB) is the deadliest bacterial disease in the world. New therapeutic agents are urgently needed to replace existing drugs for which resistance is a significant problem. DNA topoisomerases are well-validated targets for antimicrobial and anticancer chemotherapies. Although bacterial topoisomerase I has yet to be exploited as a target for clinical antibiotics, DNA gyrase has been extensively targeted, including the highly clinically successful fluoroquinolones, which have been utilized in TB therapy...
November 14, 2016: Drug Discovery Today
T Schön, P Miotto, C U Köser, M Viveiros, E Böttger, E Cambau
Drug-resistance testing, or antimicrobial susceptibility testing (AST), is mandatory for Mycobacterium tuberculosis in cases of failure on standard therapy. We reviewed the different methods and techniques of phenotypic and genotypic approaches. Although multiresistant and extensively drug-resistant (MDR/XDR) tuberculosis is present worldwide, AST for M. tuberculosis (AST-MTB) is still mainly performed according to the resources available rather than the drug-resistance rates. Phenotypic methods, i.e. culture-based AST, are commonly used in high-income countries to confirm susceptibility of new cases of tuberculosis...
November 1, 2016: Clinical Microbiology and Infection
Madhukar Pai, Marcel A Behr, David Dowdy, Keertan Dheda, Maziar Divangahi, Catharina C Boehme, Ann Ginsberg, Soumya Swaminathan, Melvin Spigelman, Haileyesus Getahun, Dick Menzies, Mario Raviglione
Tuberculosis (TB) is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body. Infection with M. tuberculosis can evolve from containment in the host, in which the bacteria are isolated within granulomas (latent TB infection), to a contagious state, in which the patient will show symptoms that can include cough, fever, night sweats and weight loss. Only active pulmonary TB is contagious...
October 27, 2016: Nature Reviews. Disease Primers
Navisha Dookie, A Willem Sturm, Prashini Moodley
BACKGROUND: In South Africa, drug resistant tuberculosis is a major public health crisis in the face of the colossal HIV pandemic. METHODS: In an attempt to understand the distribution of drug resistance in our setting, we analysed the rpoB, katG, inhA, pncA and embB genes associated with resistance to key drugs used in the treatment of tuberculosis in clinical isolates of Mycobacterium tuberculosis in the KwaZulu-Natal province. RESULTS: Classical mutations were detected in the katG, inhA and embB genes associated with resistance to isoniazid and ethambutol...
October 26, 2016: BMC Infectious Diseases
Jennifer Herrmann, Tadeja Lukežič, Angela Kling, Sascha Baumann, Stephan Hüttel, Hrvoje Petković, Rolf Müller
Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery...
October 15, 2016: Current Topics in Microbiology and Immunology
Bintou A Ahidjo, Mariama C Maiga, Elizabeth A Ihms, Mamoudou Maiga, Alvaro A Ordonez, Laurene S Cheung, Sarah Beck, Bruno B Andrade, Sanjay Jain, William R Bishai
Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone's antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response...
September 8, 2016: JCI Insight
Yanan Li, Yuling Wang, Zhi Zhang, Huixia Gao, Haibin Wang, Jinfeng Cao, Shumin Zhang, Yuzhen Liu, Jianhua Lu, Zungui Xu, Erhei Dai
Ethambutol (EMB) is an essential first-line drug for tuberculosis (TB) treatment. Nucleotide substitutions at embB codon 306 (embB306) have been proposed to be a potential marker for EMB resistance and a predictor of broad drug resistance in clinical Mycobacterium tuberculosis isolates. However, discordant findings about the association between embB306 mutations and EMB resistance were reported. Hebei Province is located in the Beijing-Tianjin-Hebei integration region in China; however, little information about the genetic diversity of the embB locus in this area is available...
December 2016: Antimicrobial Agents and Chemotherapy
Saurabh Garg, Neeraj Shakya, Naveen C Srivastav, Babita Agrawal, Dennis Y Kunimoto, Rakesh Kumar
The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6-10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30-33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays...
November 1, 2016: Bioorganic & Medicinal Chemistry
Mark P Pereira, Julie Shi, Shana O Kelley
Mycobacterial infections are difficult to treat due to the bacterium's slow growth, ability to reside in intracellular compartments within macrophages, and resistance mechanisms that limit the effectiveness of conventional antibiotics. Developing antibiotics that overcome these challenges is therefore critical to providing a pipeline of effective antimicrobial agents. Here, we describe the synthesis and testing of a unique peptide-drug conjugate that exhibits high levels of antimicrobial activity against M...
December 11, 2015: ACS Infectious Diseases
Prudence N Kabongo-Kayoka, Jacobus N Eloff, Chikwelu L Obi, Lyndy J McGaw
Treatment of tuberculosis (TB) is a challenge because of multidrug-resistant and extremely drug-resistant strains of Mycobacterium tuberculosis. Plant species contain antimicrobial compounds that may lead to new anti-TB drugs. Previous screening of some tree species from the Anacardiaceae family revealed the presence of antimicrobial activity, justifying further investigations. Leaf extracts of 15 Anacardiaceae tree species were screened for antimycobacterial activity using a twofold serial microdilution assay against the pathogenic Mycobacterium bovis and multidrug resistant M...
September 13, 2016: Phytotherapy Research: PTR
Sridhara Janardhan, M Ram Vivek, G Narahari Sastry
The emergence of drug resistant strains of Mycobacterium Tuberculosis (Mtb) accentuates the urgent need for the development of novel antitubercular drugs. The major causes of drug resistance are genetic mutations, the influx-efflux transporter system, and the complex cell wall system of Mtb, which can function as permeability barriers. The driving force for permeability of small molecules through a biological system depends on various physicochemical factors. To understand the permeability of small molecules and subsequent cell inhibition, we have developed predictive QSAR models based on reported enzyme-based (IC50) and cell-based (MIC) Mtb inhibitory data...
October 18, 2016: Molecular BioSystems
Helmut J F Salzer, Nasstasja Wassilew, Niklas Köhler, Ioana D Olaru, Gunar Günther, Christian Herzmann, Barbara Kalsdorf, Patricia Sanchez-Carballo, Elena Terhalle, Thierry Rolling, Christoph Lange, Jan Heyckendorf
Chronic respiratory infectious diseases are causing high rates of morbidity and mortality worldwide. Tuberculosis, a major cause of chronic pulmonary infection, is currently responsible for approximately 1.5 million deaths per year. Although important advances in the fight against tuberculosis have been made, the progress towards eradication of this disease is being challenged by the dramatic increase in multidrug-resistant bacilli. Nontuberculous mycobacteria causing pulmonary disease and chronic pulmonary aspergillosis are emerging infectious diseases...
2016: Respiration; International Review of Thoracic Diseases
Kerri M Malone, Stephen V Gordon
In new research on Mycobacterium tuberculosis, the causative agent of tuberculosis, Warrier and colleagues have discovered a novel mode of bacterial drug resistance, namely antibiotic inactivation via N-methylation.
October 2016: Trends in Microbiology
Divakar Sharma, Manju Lata, Mohammad Faheem, Asad Ullah Khan, Beenu Joshi, Krishnamurthy Venkatesan, Sangeeta Shukla, Deepa Bisht
Tuberculosis is an infectious disease, caused by one of the most successful human pathogen, Mycobacterium tuberculosis. Aminoglycosides, Amikacin (AK) & Kanamycin (KM) are commonly used to treat drug resistant tuberculosis. They target the protein synthesis machinery by interacting with several steps of translation. Several explanations have been proposed to explain the mechanism of aminoglycoside resistance but still our information is inadequate. Iron storing/interacting proteins were found to be overexpressed in aminoglycosides resistant isolates...
September 16, 2016: Biochemical and Biophysical Research Communications
Jun-Jie Koh, Hanxun Zou, Devika Mukherjee, Shuimu Lin, Fanghui Lim, Javey Khiapeng Tan, Dhi-Zen Tan, Bridget L Stocker, Mattie S M Timmer, Hilary M Corkran, Rajamani Lakshminarayanan, Donald T H Tan, Derong Cao, Roger W Beuerman, Thomas Dick, Shouping Liu
Tuberculosis (TB) remains a deadly disease and infects one-third of the world's population. Given the low success rates encountered in clinical development, there is an urgent need to identify structurally novel antimicrobials for tuberculosis. The present report details the anti-mycobacterial activities, structure-activity relationships (SARs) and mechanism of action of amphiphilic xanthone derivatives. The xanthones exhibited potent MIC, rapid time-kill and no cross-resistance with the current anti-TB drugs...
November 10, 2016: European Journal of Medicinal Chemistry
Noton K Dutta, Rongjun He, Michael L Pinn, Yantao He, Francis Burrows, Zhong-Yin Zhang, Petros C Karakousis
Novel drugs are required to shorten the duration of treatment for tuberculosis (TB) and to combat the emergence of drug resistance. One approach has been to identify and target Mycobacterium tuberculosis (Mtb) virulence factors, which promote the establishment of TB infection and pathogenesis. Mtb produces a number of virulence factors, including two protein tyrosine phosphatases (PTPs), mPTPA and mPTPB, to evade the antimicrobial functions of host macrophages. To assess the therapeutic potential of targeting the virulent Mtb PTPs, we developed highly potent and selective inhibitors of mPTPA (L335-M34) and mPTPB (L01-Z08) with drug-like properties...
March 11, 2016: ACS Infectious Diseases
T Parumasivam, J G Y Chan, A Pang, D H Quan, J A Triccas, W J Britton, H K Chan
Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine...
October 2016: European Journal of Pharmaceutics and Biopharmaceutics
Rickey P Hicks
Eleven antimicrobial peptides (AMP) based on the incorporation of cyclic tetra substituted C(α) amino acids, as well as other unnatural amino acids were designed, synthesized and screened for in vitro activity against 18 strains of bacteria as well as 12 cancer cell lines. The AMPs discussed herein are derived from the following peptide sequence: Ac-GF(X)G(X)B(X)G(X)F(X)G(X)GB(X)BBBB-amide, X=any one of the following residues, A5c, A6c, Tic or Oic and B=any one of the following residues, Arg, Lys, Orn, Dpr or Dab...
September 15, 2016: Bioorganic & Medicinal Chemistry
Qiming Li, Mingliang Zhou, Xiangyu Fan, Jianlong Yan, Weimin Li, Jianping Xie
M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS...
2016: Scientific Reports
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