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Mycobacterium tuberculosis AND drug use and [keywords]
- Specific Interaction between Mycobacterium tuberculosis Lipoprotein-derived Peptides and Target Cells Inhibits Mycobacterial Entry In Vitro. [JOURNAL ARTICLE]
- Chem Biol Drug Des 2014 Jul 10.
Tuberculosis (TB) continues being one of the diseases having the greatest mortality rates around the world, 8.7 million cases having been reported in 2011. An efficient vaccine against TB having a great impact on public health is an urgent need. Usually, selecting antigens for vaccines has been based on proteins having immunogenic properties for patients suffering TB and having had promising results in mice and non-human primates. Our approach has been based on a functional approach involving the pathogen-host interaction in the search for antigens to be included in designing an efficient, minimal, subunit-based anti-TB vaccine. This means that Mycobacterium tuberculosis has mainly been involved in studies and that lipoproteins represent an important kind of protein on the cell envelope which can also contribute towards this pathogen's virulence. This study has assessed the expression of four lipoproteins from M. tuberculosis H37Rv, that is, Rv1411c (LprG), Rv1911c (LppC), Rv2270 (LppN) and Rv3763 (LpqH), and the possible biological activity of peptides derived from these. Five peptides were found for these proteins which had high specific binding to both alveolar A549 epithelial cells and U937 monocyte-derived macrophages which were able to significantly inhibit mycobacterial entry to these cells in vitro.
- EspI regulates the ESX-1 secretion system in response to ATP levels in Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- Mol Microbiol 2014 Jul 15.
The function of EspI, a 70-kDa protein in Mycobacterium tuberculosis, has remained unclear. Although EspI is encoded by a gene within the esx-1 locus, in this study we clarify previous conflicting results and show that EspI is not essential for ESX-1-mediated secretion or virulence in M. tuberculosis. We also provide evidence that reduction of cellular ATP levels in wild-type M. tuberculosis using the drug bedaquiline completely blocks ESX-1-mediated secretion. Remarkably, M. tuberculosis lacking EspI fails to exhibit this phenotype. Furthermore, mutagenesis of a highly conserved ATP-binding motif in EspI renders M. tuberculosis incapable of shutting down ESX-1-mediated secretion during ATP depletion. Collectively these results show that M. tuberculosis EspI negatively regulates the ESX-1 secretion system in response to low cellular ATP levels and this function requires the ATP-binding motif. In light of our results the potential significance of EspI in ESX-1 function during latent tuberculosis infection and reactivation is also discussed.
- A close-up on the epidemiology and transmission of multidrug-resistant tuberculosis in Poland. [JOURNAL ARTICLE]
- Eur J Clin Microbiol Infect Dis 2014 Jul 20.
Multidrug-resistant tuberculosis (MDR-TB) poses a serious challenge to the global control of the disease. The purpose of this study was to characterize MDR-TB patients from Poland and to determine the extent of MDR-TB disease attributable to recent transmission. The study included all 46 patients diagnosed with MDR-TB in Poland in 2004 and followed up for 6 years (until 2011). For each patient, sociodemographic and clinical characteristics, treatment outcomes, and bacteriological data were collected by the review of medical and laboratory records. Mycobacterium tuberculosis isolates from all patients were characterized using spoligotyping, mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing, IS6110 restriction fragment length polymorphism (RFLP) analysis, and sequencing analysis of drug resistance-associated loci (katG, mabA-inhA, rpoβ, rpsL, and embB). The majority of patients were male (86.9 %), 40-64 years of age (60.8 %), with a history of TB treatment (84.8 %), and producing smear-positive sputa (86.9 %). Twenty-two (47.8 %) patients suffered from concomitant diseases and 28 (60.8 %) were alcohol abusers. Treatment outcome assessment revealed that 8 (17.4 %) patients were cured or completed therapy, while 15 (32.6 %) died of TB, 11 (23.9 %) defaulted, 8 (17.4 %) failed, and 1 (2.2 %) was transferred and lost to follow-up. Upon genotyping, 10 (21.7 %) isolates were allocated in four clusters. These were further subdivided by mutational profiling. Overall, in 6 (13 %) patients, MDR-TB was a result of recent transmission. For 4 (8.7 %) of these patients, a direct epidemiological link was established. The study shows that the transmission of MDR-TB occurs at a low rate in Poland. Of urgent need is the implementation of a policy of enforced treatment of MDR-TB patients in Poland.
- High Throughput Screen Identifies Small Molecule Inhibitors Specific for Mycobacterium tuberculosis Phosphoserine Phosphatase. [JOURNAL ARTICLE]
- J Biol Chem 2014 Jul 18.
The emergence of drug resistant strains of Mycobacterium tuberculosis (M. tuberculosis) makes identification and validation of newer drug targets a global priority. Phosphoserine phosphatase (PSP), a key essential metabolic enzyme involved in conversion of O-phospho-L-serine to L-serine was characterized in this study. The M. tuberculosis genome harbors all enzymes involved in L-serine biosynthesis including 2 PSP homologs, Rv0505c (SerB1) and Rv3042c (SerB2). In the present study we have biochemically characterized SerB2 enzyme and developed malachite green based high throughput assay system (HTS) to identify SerB2 inhibitors. We have identified 10 compounds that were structurally different from known PSP inhibitors and few of these scaffolds were highly specific in their ability to inhibit SerB2 enzyme, non-cytotoxic against mammalian cell lines and inhibited M. tuberculosis growth in vitro. Surface plasma resonance experiments demonstrated the relative binding for these inhibitors. The two best hits identified in our screen, clorobiocin and rosaniline were bactericidal in activity and killed intracellular bacteria in a dose dependent manner. We have also identified amino acid residues critical for these SerB2-small molecule interactions. This is the first study where we validate that M. tuberculosis SerB2 is a druggable and suitable target to pursue for further HTS screening.
- Inactivation of the Mycobacterium tuberculosis Antigen 85 complex by covalent, allosteric inhibitors. [JOURNAL ARTICLE]
- J Biol Chem 2014 Jul 14.
The rise of multidrug and totally drug-resistant tuberculosis (TB) and the association with an increasing number of HIV-positive patients developing TB emphasizes the necessity to find new antitubercular targets and drugs. The antigen 85 (Ag85) complex from Mycobacterium tuberculosis plays important roles in the biosynthesis of major components of the mycobacterial cell envelope. For this reason, Ag85 has emerged as an attractive drug target. Recently, ebselen was identified as an effective inhibitor of the Ag85 complex through covalent modification of a cysteine residue proximal to the Ag85 active site and is therefore a covalent, allosteric inhibitor. To expand the understanding of this process, we have solved the X-ray crystal structures of Ag85C covalently modified with ebselen and other thiol-reactive compounds, p-chloromercuribenzoic acid and iodoacetamide, as well as the structure of a cysteine to glycine mutant. All four structures confirm that chemical modification or mutation at this particular cysteine residue leads to the disruption of the active site hydrogen-bonded network essential for Ag85 catalysis. We also describe X-ray crystal structures of Ag85C single mutants within the catalytic triad and show that a mutation of any one of these three residues promotes the same conformational change observed in the cysteine modified forms. These results provide evidence for active site dynamics that may afford new strategies for the development of selective and potent Ag85 inhibitors.
- A Mycobacterium tuberculosis Cytochrome bd Oxidase Mutant Is Hypersensitive to Bedaquiline. [Journal Article]
- MBio 2014; 5(4)
The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery.A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy.
- Resistance to First-Line Antituberculosis Drugs in Spain, 2010-2011. RETUBES Study. [JOURNAL ARTICLE]
- Arch Bronconeumol 2014 Jul 11.
The magnitude of current resistance to antituberculosis drugs in Spain is unknown. The objective of this study is to describe resistance to first-line antituberculosis drugs and determine the associated factors.Prospective multicenter study of adult tuberculosis patients with positive Mycobacterium tuberculosis culture and antibiogram including first-line drugs in 32 hospitals and one out-patient center of the Spanish Health System between 2010 and 2011.A total of 519 patients, 342 Spanish nationals and 177 (34.1%) foreigners were studied. Drug resistance was found in 48 (9.2%), of which 35 (6.7%) were isoniazid-resistant. There were 10 (1.9%) multiresistant cases and no strain was extremely resistant. Initial isoniazid resistance was detected in 28 of the 487 (5.7%) antituberulosis-naïve patients, most of whom were foreigners (P<.01). Acquired resistance was seen in 7 (22.6%) previously treated cases. Multiresistance was initial in 6 cases (1.2%) and acquired in another 4 (12.9%). Factors associated with initial isoniazid resistance were immigrant status and group cohabitation OR=2.3; 95%CI: .98-5.67 and OR=2.2; 95%CI: 1.05-7.07 respectively). The factor associated with acquired resistance to isoniazid was age below 50 years (P=.03).The rate of initial isoniazid resistance is greater than estimated, probably due to the increase in immigration during recent years, suggesting that systematic national monitoring is required. Immigrants and those who cohabit in groups have a higher risk of isoniazid resistance.
- Tuberculosis in Papua New Guinea: from yesterday until today. [JOURNAL ARTICLE]
- Microbes Infect 2014 Jul 12.
Little is known about the situation of tuberculosis in Papua New Guinea despite its high TB burden, emerging drug resistance and rising HIV co-infection. This review gives an overview on the current situation of TB in PNG and identifies knowledge gaps that should urgently be addressed in the future.
- Comparison of different drug susceptibility test methods to detect the rifampin heteroresistance in Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Jul 14.
We compared the efficiency of different drug susceptibility testing methods to detect the rifampin (RIF) heteroresistance in Mycobacterium tuberculosis. Our data revealed that broth dilution method found more resistance than MGIT (P=0.046) for low resistance group. Similarly, broth dilution method was more sensitive to detect RIF heteroresistance in subpopulation with slow grow rate than MGIT (P=0.033). In conclusion, our data demonstrated that the broth dilution method was more sensitive than MGIT to detect RIF heteroresistance.
- Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy. [JOURNAL ARTICLE]
- Mol Immunol 2014 Jul 11; 62(1):159-168.
Active pulmonary tuberculosis (APTB) is associated with a failure of the host immune system to control the invading Mycobacterium tuberculosis (Mtb). The objective of this study was to quantify and assess the role of serum inflammatory cytokines in active pulmonary tuberculosis patients following anti-tuberculosis drug (ATD) therapy. Blood samples were collected from APTB patients and normal healthy subjects (NHS) (total n=204) at baseline and 2, 4 and 6 months post-therapy and the abundance of serum inflammatory cytokines were measured by cytokine specific ELISA. Compared to NHS, APTB patients at baseline had higher levels of serum pro-inflammatory cytokines IL-12p40 (P<0.001), IFN-γ (P<0.001), TNF-α (P<0.01), IL-1β (P<0.001) and IL-6 (P<0.001) and anti-inflammatory cytokines IL-10 (P<0.001) and TGF-β1 (P<0.001) while there was no change in the level of IL-4. In APTB patients, the serum levels of IFN-γ, TNF-α, IL-6 and TGF-β1 directly relate to the bacterial load while the TNF-α, IL-1β, IL-6 and TGF-β1 relate to radiological severity. At baseline, the IL-6 level in NHS and APTB patients differed most and following ATD therapy, this level rapidly decreased and stabilized by 4-month in APTB patients. It is concluded that a subtle reduction in the serum level of IL-6 of the APTB patients following ATD therapy might play a vital role in immune-protection of the host against Mtb infection and hence the serum IL-6 level can be a useful marker to diagnose the effectiveness of therapy in the patients.