scholarly journals Triosephosphate Isomerase from Mycobacterium tuberculosis as Potential Target to Develop a New Anti-TB Drug

2021 ◽  
Vol 12 (4) ◽  
pp. 5672-5697
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Therapeutic Target ◽  
Triosephosphate Isomerase ◽  
Glycolytic Enzyme ◽  
New Drugs ◽  
World Health ◽  
Resistant Tuberculosis ◽  
The World

Tuberculosis (TB) is possibly the most prevalent infectious disease in the world, reports from the World Health Organization (WHO) indicate that TB is one of the top 10 causes of death and an estimated 10 million people worldwide, in addition, there are increasing the TB resistant to conventional antibiotics, multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Lastly, TB has become more important and requires more attention since it has been proposed as a risk factor for the severity of COVID-19. Therefore, the need to develop new anti-TB drugs. In this study, we propose to use the glycolytic enzyme triosephosphate isomerase from Mycobacterium tuberculosis (MtTIM) as a therapeutic target against TB. The triosephosphate isomerase (TIM) is a target used in different proposals to develop new drugs against different organisms. The MtTIM is an extremely attractive drug target due to the characteristics of its amino acids sequence. In addition, it has been determined that this enzyme (MtTIM) is necessary for the viability of in vitro and in vivo cultures of Mycobacterium tuberculosis. In this way, using the MtTIM as a therapeutic target, we propose potential compounds against MtTIM by molecular docking.

Antimicrobial peptides for the treatment of pulmonary tuberculosis, allies or foes?

2018 ◽  
Vol 24 (10) ◽  
pp. 1138-1147
Author(s):  
Bruno Rivas-Santiago ◽  
Flor Torres-Juarez
Keyword(s):  
Pulmonary Tuberculosis ◽  
Antimicrobial Peptides ◽  
Experimental Models ◽  
New Drugs ◽  
World Health ◽  
Public Health Issue ◽  
Health Organization ◽  
Drug Resistant Strains

Tuberculosis is an ancient disease that has become a serious public health issue in recent years, although increasing incidence has been controlled, deaths caused by Mycobacterium tuberculosis have been accentuated due to the emerging of multi-drug resistant strains and the comorbidity with diabetes mellitus and HIV. This situation is threatening the goals of World Health Organization (WHO) to eradicate tuberculosis in 2035. WHO has called for the creation of new drugs as an alternative for the treatment of pulmonary tuberculosis, among the plausible molecules that can be used are the Antimicrobial Peptides (AMPs). These peptides have demonstrated remarkable efficacy to kill mycobacteria in vitro and in vivo in experimental models, nevertheless, these peptides not only have antimicrobial activity but also have a wide variety of functions such as angiogenesis, wound healing, immunomodulation and other well-described roles into the human physiology. Therapeutic strategies for tuberculosis using AMPs must be well thought prior to their clinical use; evaluating comorbidities, family history and risk factors to other diseases, since the wide function of AMPs, they could lead to collateral undesirable effects.

scholarly journals GeneXpert MTB/RIF Assay for Rapid Identification of Mycobacterium Tuberculosis and Rifampicin Resistance Directly from Sputum Sample

2017 ◽  
Vol 7 (2) ◽  
pp. 86-89 ◽  
Author(s):  
Nourjahan Laskar ◽  
Md Akram Hossain ◽  
Jannatul Fardows ◽  
Mominur Rahman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sputum Sample ◽  
Rapid Identification ◽  
Rapid Diagnosis ◽  
World Health ◽  
Multi Drug Resistance ◽  
Drug Resistant ◽  
Resistant Tuberculosis ◽  
The World ◽  
Health Organization

Background: The World Health Organization has endorsed the use of molecular methods for the detection of tuberculosis (TB) and drug resistant TB as a rapid method. In Bangladesh, the Xpert MTB/RIF assay has been implemented into reference laboratories for diagnosis of TB and also MDR TB.Objective: Drug resistant tuberculosis has long been a common problem prevailing in our country. The present study focused on the rapid identification of Mycobacterium tuberculosis as well as drug resistance.Materials and Methods: Sputum samples from a total of 107 cases, assumed as multi-drug resistance tuberculosis, were studied through GeneXpert assay.Results: Out of 107 cases, 91 (85.05%) were detected having M. tuberculosis ? 64 (59.81%) were rifampicin sensitive and 27 (25.23%) were rifampicin resistant. The sensitivity and specificity of the GeneXpert are 87.64% and 75% respectively.Conclusion: GeneXpert assay can be considered for the rapid diagnosis of drug resistant tuberculosis.J Enam Med Col 2017; 7(2): 86-89

scholarly journals Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

2015 ◽  
Vol 59 (8) ◽  
pp. 4457-4463 ◽  
Author(s):  
Benoit Lechartier ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Drug Resistant Strains ◽  
Transfer Chain

ABSTRACTClofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. InMycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O2. CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM againstM. tuberculosisand found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergisticin vitrowith benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was testedin vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains ofM. 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.

scholarly journals Activity of ketoconazole against Mycobacterium tuberculosis in vitro and in the mouse model

2007 ◽  
Vol 56 (8) ◽  
pp. 1047-1051 ◽  
Author(s):  
Sean T. Byrne ◽  
Steven M. Denkin ◽  
Peihua Gu ◽  
Eric Nuermberger ◽  
Ying Zhang
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Term Treatment ◽  
New Drugs ◽  
Bacteriostatic Effect ◽  
Short Term ◽  
Short Term Treatment ◽  
Neutral Conditions

There is an urgent need for the development of new drugs that are active against drug-resistant Mycobacterium tuberculosis strains and can shorten tuberculosis (TB) therapy. It has previously been reported that the azole class of antifungals has anti-TB activity in vitro. This study evaluated ketoconazole (KTC) for activity against M. tuberculosis. The MIC of KTC for different M. tuberculosis strains ranged from 8 to 16 μg ml−1 under both acidic and neutral conditions, with the minimum bactericidal concentration being about twofold higher than the MIC. KTC had enhanced activity against old, non-growing bacilli in vitro when combined with pyrazinamide (PZA) and rifampicin (RIF). A single oral dose of KTC at 75 mg kg−1 led to an inhibitory serum concentration 2 h after administration. The in vivo activity of KTC was evaluated in established pulmonary TB in the murine model, compared alone and in combination with isoniazid (INH), PZA and RIF. KTC alone exhibited little effect after short-term treatment, with a borderline bacteriostatic effect on spleen colony counts but not on lung counts. KTC, when added in combination with INH, PZA and RIF, significantly improved the treatment outcome in the lungs (compared with treatment with INH, PZA and RIF). The lowest numbers of bacilli in lungs were found in mice treated with KTC, PZA and RIF. Further investigation is necessary to determine the role of KTC in the treatment of TB.

Recent Development of Coumarin Derivatives as Potential Antiplasmodial and Antimalarial Agents

2018 ◽  
Vol 18 (2) ◽  
pp. 114-123 ◽  
Author(s):  
Xin-Liang Hu ◽  
Chuan Gao ◽  
Zhi Xu ◽  
Ming-Liang Liu ◽  
Lian-Shun Feng ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Malaria Control ◽  
Biological Properties ◽  
New Drugs ◽  
Coumarin Derivatives ◽  
Antimalarial Agents ◽  
Structure Activity ◽  
The World

Malaria still remains one of the leading deadliest diseases throughout the world, leading to around 1 million deaths annually. The emergence and spread of growing resistance to the firstline antimalarials are an alarming the serious problem in malaria control, demanding the need for new drugs more potent than earlier with improved Absorption, Distribution, Metabolism, and Excretion (ADME) profiles. Coumarins, which exhibited various biological properties, also displayed potential in vitro antiplasmodial and in vivo antimalarial activities. Moreover, many of coumarin derivatives have already been used in clinical practice for the treatment of several diseases. Therefore, coumarin derivatives play a pivotal role in medicinal chemistry, also making them promising candidates for the treatment of malaria. This review aims to summarize the recent advances made towards the development of coumarin-containing derivatives as antiplasmodial and antimalarial agents and their structure-activity relationship is also discussed.

scholarly journals Dietary Anthocyanins and Stroke: A Review of Pharmacokinetic and Pharmacodynamic Studies

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1479 ◽  
Author(s):  
Manolescu ◽  
Oprea ◽  
Mititelu ◽  
Ruta ◽  
Farcasanu
Keyword(s):  
Stroke Prevention ◽  
Mechanisms Of Action ◽  
World Health ◽  
Pharmacokinetic Studies ◽  
Cerebrovascular Accidents ◽  
The Third ◽  
The World ◽  
Health Organization

Cerebrovascular accidents are currently the second major cause of death and the third leading cause of disability in the world, according to the World Health Organization (WHO), which has provided protocols for stroke prevention. Although there is a multitude of studies on the health benefits associated with anthocyanin (ACN) consumption, there is no a rigorous systematization of the data linking dietary ACN with stroke prevention. This review is intended to present data from epidemiological, in vitro, in vivo, and clinical studies dealing with the stroke related to ACN-rich diets or ACN supplements, along with possible mechanisms of action revealed by pharmacokinetic studies, including ACN passage through the blood-brain barrier (BBB).

scholarly journals The Combination of Sulfamethoxazole, Trimethoprim, and Isoniazid or Rifampin Is Bactericidal and Prevents the Emergence of Drug Resistance in Mycobacterium tuberculosis

2012 ◽  
Vol 56 (10) ◽  
pp. 5142-5148 ◽  
Author(s):  
Catherine Vilchèze ◽  
William R. Jacobs
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Drug Resistant ◽  
Content Type ◽  
The Past ◽  
Tb Treatment

ABSTRACTThe challenges of developing new drugs to treat tuberculosis (TB) are indicated by the relatively small number of candidates entering clinical trials in the past decade. To overcome these issues, we reexamined two FDA-approved antibacterial drugs, sulfamethoxazole (SMX) and trimethoprim (TMP), for use in TB treatment. SMX and TMP inhibit folic acid biosynthesis and are used in combination to treat infections of the respiratory, urinary, and gastrointestinal tracts. The MICs of SMX and TMP, alone and in combination, were determined for drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistantMycobacterium tuberculosisstrains. While TMP alone was not effective againstM. tuberculosis, the combination of TMP and SMX was bacteriostatic againstM. tuberculosis. Surprisingly, the combination of SMX and TMP was also active against a subset of MDRM. tuberculosisstrains. Treatment ofM. tuberculosiswith TMP-SMX and a first-line anti-TB drug, either isoniazid or rifampin, was bactericidal, demonstrating that the combination of TMP and SMX with isoniazid or rifampin was not antagonistic. Moreover, the addition of SMX-TMP in combination with either isoniazid or rifampin also prevented the emergence of drug resistancein vitro. In conclusion, this study further illustrates the opportunity to reevaluate the activity of TMP-SMXin vivoto prevent the emergence of drug-resistantM. tuberculosis.

scholarly journals Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis

2018 ◽  
Vol 63 (2) ◽  
pp. e01489-18 ◽  
Author(s):  
Sander P. van Rijn ◽  
Marlanka A. Zuur ◽  
Richard Anthony ◽  
Bob Wilffert ◽  
Richard van Altena ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
International Travel ◽  
Future Research ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Susceptibility Tests

ABSTRACT Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis. To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.

scholarly journals In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Jian Xu ◽  
Bin Wang ◽  
Lei Fu ◽  
Hui Zhu ◽  
Shaochen Guo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Skin Pigmentation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Resistant Tuberculosis ◽  
Wild Strains ◽  
Skin Discoloration ◽  
Aerosol Infection

ABSTRACT The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. The in vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 × 10−7 in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.

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