scholarly journals Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy

2021 ◽  
Author(s):  
Lloyd Tanner ◽  
Gabriel T. Mashabela ◽  
Charles C. Omollo ◽  
Timothy J. de Wet ◽  
Christopher J. Parkinson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Resistant ◽  
Intracellular Accumulation ◽  
First Line ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Therapeutic Compounds ◽  
Novel Therapeutic

This study addresses the development of novel therapeutic compounds for the eventual treatment of drug-resistant tuberculosis. Tuberculosis continues to progress, with cases of Mycobacterium tuberculosis ( M. tuberculosis ) resistance to first-line medications increasing.

scholarly journals Bazedoxifene Suppresses Intracellular Mycobacterium tuberculosis Growth by Enhancing Autophagy

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Qi Ouyang ◽  
Kehong Zhang ◽  
Dachuan Lin ◽  
Carl G. Feng ◽  
Yi Cai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
New Host ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Receptor Modulator ◽  
Resistant Tuberculosis ◽  
Negative Side Effects

ABSTRACT Tuberculosis (TB) is still the leading killer caused by Mycobacterium tuberculosis infection. There is a clear need for new treatment strategy against TB. It has been reported that tamoxifen, known as a selective estrogen receptor modulator (SERM), exhibits antimycobacterial activity and inhibits M. tuberculosis growth in macrophages. However, it remains unknown whether such antimicrobial activity is a general property of all SERMs and how it works. In this study, we identified that bazedoxifene (BZA), a newer SERM, inhibits intracellular M. tuberculosis growth in macrophages. BZA treatment increases autophagosome formation and LC3B-II protein expression in M. tuberculosis-infected macrophages. We further demonstrated that the enhancement of autophagy by BZA is dependent on increased reactive oxygen species (ROS) production and associated with phosphorylation of Akt/mTOR signaling. In summary, our data reveal a previously unappreciated antimicrobial function of BZA and suggest that future investigation focusing on the mechanism of action of SERMs in macrophages may lead to new host-directed therapies against TB. IMPORTANCE Since current strategies for the treatment of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have low efficacy and highly negative side effects, research on new treatments including novel drugs is essential for curing drug-resistant tuberculosis. Host-directed therapy (HDT) has become a promising idea to modulate host cell responses to enhance protective immunity against pathogens. Bazedoxifene (BZA), which belongs to a new generation of SERMs, shows the ability to inhibit the growth of M. tuberculosis in macrophages and is associated with autophagy. Our findings reveal a previously unrecognized antibacterial function of BZA. We propose that the mechanism of SERMs action in macrophages may provide a new potential measure for host-directed therapies against TB.

scholarly journals Meropenem-Clavulanic Acid Has HighIn VitroActivity against Multidrug-Resistant Mycobacterium tuberculosis

2015 ◽  
Vol 59 (6) ◽  
pp. 3630-3632 ◽  
Author(s):  
L. Davies Forsman ◽  
C. G. Giske ◽  
J. Bruchfeld ◽  
T. Schön ◽  
P. Juréen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clavulanic Acid ◽  
Treatment Option ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Potential Treatment ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

ABSTRACTWe investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68Mycobacterium tuberculosisisolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB.

Transmission of multi-drug resistant tuberculosis in Mongolia is driven by Beijing strains of Mycobacterium tuberculosis resistant to all first-line drugs

Tuberculosis ◽  
2016 ◽  
Vol 101 ◽  
pp. 49-53 ◽  
Author(s):  
Ulziijargal Gurjav ◽  
Baasansuren Erkhembayar ◽  
Buyankhishig Burneebaatar ◽  
Erdenegerel Narmandakh ◽  
Oyuntuya Tumenbayar ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Resistant ◽  
First Line ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multi Drug Resistant Tuberculosis

scholarly journals Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic

2014 ◽  
Vol 59 (2) ◽  
pp. 1308-1319 ◽  
Author(s):  
Neeraj Dhar ◽  
Vincent Dubée ◽  
Lluis Ballell ◽  
Guillaume Cuinet ◽  
Jean-Emmanuel Hugonnet ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Cells ◽  
Alternative Therapy ◽  
Potential Candidate ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Lactam Antibiotic ◽  
Orally Bioavailable

ABSTRACTRecent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently killsMycobacterium tuberculosiseven in the absence of clavulanate. The target enzymes,l,d-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.

scholarly journals Use of fluorescein diacetate (FDA) staining to detect viable Mycobacterium tuberculosis

2012 ◽  
Vol 11 (4) ◽  
pp. 322-330 ◽  
Author(s):  
Shamima Islam ◽  
Farjana Rahman ◽  
Saurab Kisore Munshi ◽  
Jewel Ahmed ◽  
S M Mostafa Kamal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Failure ◽  
Medical Science ◽  
Multidrug Resistant ◽  
Fluorescein Diacetate ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Auramine O

Objective: Drug resistant tuberculosis has long been a common problem prevailing in developing countries including Bangladesh. Present study focused on the rapid identification of live Mycobacterium tuberculosis among treatment failure cases.Materials and Methods: Sputum samples from a total of 100 category-I and category-II treatment failure cases, assumed as multidrug resistant tuberculosis, were studied through fluorescein diacetate (FDA) staining under light emitting diode (LED) fluorescence microscope. Considering culture method as gold standard, we also compared the results of FDA staining with that of auramine O staining.Results: A total of 85% acid-fast bacilli were detected by FDA staining, 82% by auramine O staining and a total of 85% isolates were detected in Lowenstein-Jensen (LJ) culture. The sensitivity of FDA staining (96.47%) was estimated to be slightly higher than that of auramine O staining (91.76%). Moreover,76.47% cases were detected as multidrug resistant tuberculosis (MDR-TB). Conclusion: Taken together, FDA staining method has been proposed to be appropriate for the rapid diagnosis of drug resistant tuberculosis. DOI: http://dx.doi.org/10.3329/bjms.v11i4.12605 Bangladesh Journal of Medical Science Vol. 11 No. 04 Oct’12

scholarly journals Prevalence of primary drug resistant tuberculosis in a tertiary care hospital, Nepal

2015 ◽  
Vol 4 (4) ◽  
pp. 36-38
Author(s):  
R Khunjeli ◽  
U R Mohsin ◽  
S K Shrestha ◽  
S Adhikari ◽  
B Srivastava ◽  
...  
Keyword(s):  
Armed Forces ◽  
Care Hospital ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
First Line ◽  
Sensitivity Testing ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Resistant Strains ◽  
Primary Drug

 Background & objectives: Tuberculosis is a transmissible disease mainly due to inhalation of infected droplet nuclei. The burden of drug resistant tuberculosis is very high in our neighboring countries India and China. Prevalence of primary drug resistant disease is difficult to estimate in our country because culture and sensitivity is not done routinely. This study was an attempt to find out the prevalence of drug resistant in newly diagnosed tuberculosis patients serving in the Nepalese Armed Forces. Methodology: Medical records of patients serving in the Nepalese Armed Forces who had the provisional diagnosis of pulmonary tuberculosis for the first time from July 2012 to June 2014 were analyzed. They had their sputum subjected for both smear and culture with sensitivity testing. Out of 134 patients, 62 had culture positive for Mycobacterium tuberculosis and drug sensitivity was done for the first line 4 antitubercular drugs. Results: Drug resistant strains were found in 5 cases (8.1%) of which 2 (3.2%) were resistant to 4 first line drugs - rifampicin, isoniazid, ethambutol and streptomycin. Prevalence of isoniazid resistance was the highest, found in 3 cases (4.8%). Conclusion: Primary drug resistant tuberculosis in newly diagnosed cases was high even in young healthy adults, and isoniazid resistant strains were the commonest.DOI: http://dx.doi.org/10.3126/jcmc.v4i4.11970

scholarly journals Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis

2007 ◽  
Vol 51 (7) ◽  
pp. 2618-2620 ◽  
Author(s):  
Xin Shen ◽  
Guo-miao Shen ◽  
Jie Wu ◽  
Xiao-hong Gui ◽  
Xia Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Odds Ratio ◽  
Rapid Detection ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Candidate Marker ◽  
Resistant Tuberculosis

ABSTRACT embB306 mutants were detected in both ethambutol (EMB)-resistant and EMB-susceptible strains of Mycobacterium tuberculosis. Multidrug-resistant (MDR) strains had a higher proportion of embB306 mutants than non-MDR strains (odds ratio, 6.78; P < 0.001). The embB306 locus is a candidate marker for rapid detection of MDR and extremely drug resistant tuberculosis.

scholarly journals In VitroandIn VivoActivities of the Nitroimidazole TBA-354 against Mycobacterium tuberculosis

2014 ◽  
Vol 59 (1) ◽  
pp. 136-144 ◽  
Author(s):  
A. M. Upton ◽  
S. Cho ◽  
T. J. Yang ◽  
Y. Kim ◽  
Y. Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pharmacokinetic Profile ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Drug Resistant ◽  
Next Generation ◽  
Content Type ◽  
Resistant Tuberculosis

ABSTRACTNitroimidazoles are a promising new class of antitubercular agents. The nitroimidazo-oxazole delamanid (OPC-67683, Deltyba) is in phase III trials for the treatment of multidrug-resistant tuberculosis, while the nitroimidazo-oxazine PA-824 is entering phase III for drug-sensitive and drug-resistant tuberculosis. TBA-354 (SN31354[(S)-2-nitro-6-((6-(4-trifluoromethoxy)phenyl)pyridine-3-yl)methoxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine]) is a pyridine-containing biaryl compound with exceptional efficacy against chronic murine tuberculosis and favorable bioavailability in preliminary rodent studies. It was selected as a potential next-generation antituberculosis nitroimidazole following an extensive medicinal chemistry effort. Here, we further evaluate the pharmacokinetic properties and activity of TBA-354 againstMycobacterium tuberculosis. TBA-354 is narrow spectrum and bactericidalin vitroagainst replicating and nonreplicatingMycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. The addition of serum protein or albumin does not significantly alter this activity. TBA-354 maintains activity againstMycobacterium tuberculosisH37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates. Spontaneous resistant mutants appear at a frequency of 3 × 10−7.In vitrostudies andin vivostudies in mice confirm that TBA-354 has high bioavailability and a long elimination half-life.In vitrostudies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependentin vivobactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824. Its superior potency and pharmacokinetic profile that predicts suitability for once-daily oral dosing suggest that TBA-354 be studied further for its potential as a next-generation nitroimidazole.

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