Drug-sensitive Mycobacterium Tuberculosis Strains Research Articles

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives.

Tuberculosis (TB) is currently the leading cause of mortality due to an infectious disease, despite the existence of multiple effective first-line and second-line drugs. The current anti-TB regimen requires a prolonged treatment period of around 6 months and is only efficacious against drug-sensitive strains of Mycobacterium tuberculosis (Mtb). With a rise in cases of multi-drug resistant and extensively drug resistant strains of Mtb, newer treatments comprising compounds with novel mechanisms of action are required. Although decoquinate (DQ) is inactive against Mtb, its derivatives are of interest to anti-TB drug discovery because of their potential to permeate the mycobacterial cell wall, Mtb-infected macrophages, and granulomatous lesions by passive diffusion. The compounds also display mechanisms of action which are unlike those of currently used quinolones, potentially displaying activity against new targets. Three such derivatives bearing an alkyl group at N-1 and an amide group at C-3 (RMB 041, -043, and -073) displayed potent in vitro activities against Mtb H37Rv (90% minimum inhibitory concentrations, MIC90 = 1.61, 4.18, and 1.88 μM, respectively) and high selectivity indices (10–25). In this study, we evaluated the drug-like properties (in vitro microsomal stability, microsomal/plasma protein binding, kinetic solubility, lipophilicity, and passive permeability) and pharmacokinetic (PK) parameters of these compounds after intravenous and oral administration to male C57BL/6 mice. The compounds showed markedly improved kinetic solubilities compared to that of the parental DQ and were metabolically stable in vitro. The maximum concentrations reached after oral administration were 5.4 ± 0.40, 5.6 ± 1.40, and 2.0 ± 0.03 μM; elimination half-lives were 23.4 ± 2.50, 6.2 ± 0.80, and 11.6 ± 1.30 h; and bioavailabilities were 21.4 ± 1.0, 22.1 ± 2.2, and 5.9 ± 1.3 for RMB041, -043, and -073, respectively. These compounds therefore display promising drug-like properties, and their PK/toxicity profiles (including long half-lives both in vitro and in vivo) support their potential as candidates for further investigation in animal models of Mtb infection.

In vivo potent BM635 analogue with improved drug-like properties

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.

Drug-resistant TB: deadly, costly and in need of a vaccine.

TB is an underappreciated public health threat in developed nations. In 2014, an estimated 9.6 million TB cases and 1.5 million deaths occurred worldwide; 3.3% of these cases resulted from multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains. These figures underestimate the economic burden associated with MDR-TB and XDR-TB, as the cost of treating disease caused by these strains can be 9–25 times higher than treating drug-susceptible TB. Developing new drugs, improved diagnostics and new TB vaccines are critical components of a strategy to combat TB in general, and drug-resistant TB in particular. Because Mycobacterium tuberculosis (MTB) has demonstrated a capacity to develop resistance to drugs developed to combat it, it is unlikely that drug-resistant MTB would be ‘resistant’ to vaccines capable of preventing disease or established infection with drug-sensitive MTB strains. Accordingly, the development of TB vaccines represents an important long-term investment in preventing the spread of drug-resistant TB and achieving WHO's goal of ending the global TB epidemic by 2035. Our current understanding of the epidemiology of drug-resistant TB and the interventions needed to limit its spread, reviewed in this article, illustrates the need for increased financial support for developing new TB drugs, diagnostics and vaccines to meet the WHO goal of TB elimination by 2035.

Functional Analysis Using Whole-Genome Sequencing of a Drug-Sensitive Mycobacterium tuberculosis Strain from Peru

We report the whole-genome sequence of a Latin American-Mediterranean (LAM) lineage drug-sensitive Mycobacterium tuberculosis strain from Peru, INS-SEN. The functional analysis revealed more mutations in secondary metabolite biosynthesis, transport, and catabolism (clusters of orthologous groups [COG] category Q) than for other LAM-sensitive strains. This study contributes to the understanding of the genomic diversity of drug-sensitive M. tuberculosis.

Immune reconstitution syndrome (IRIS) in a child with disseminated tuberculosis

IRIS is a paradoxical reaction initially described in HIV-infected patient after initiation of antiretroviral therapy (ART). Incidence is estimated between 12 to 19% in children starting ART. TB associated IRIS is characterized by a clinical worsening after the start of ART in patients receiving Tb treatment. It can also be diagnosed as a new presentation of Tb that is “unmasked” in the weeks following initiation of ART and exclusion of other causes that could explain a deterioration (such as antimicrobial drug resistance, drug hypersensitivity reaction, or another opportunistic infection). IRIS in association with tuberculosis in non-HIV patients has not been reported in the literature. We report the case of an HIV negative 8 years-old malnourished girl of Haitian origin who developed an IRIS and dilated cardiomyopathy during her treatment for severe disseminated TB (lungs, mediastinal lymph nodes, spleen, liver and kidneys). An antibiotic treatment consisting of Rifampine, Izoniacid, Pyrazinamide and Ethambutol (RIPE) for the initial 2 months followed by months 10 of RI was begun against a drug sensitive mycobacterium tuberculosis strain retrieved in gastric aspirates and urine. The child appeared stable for the 2 first weeks of treatment but her fever kept going. In fact, fever (39–40°C) and rigors persisted on a daily basis with diffuse bone pains, elevated transaminases over the next 5 months together with an initial progression of the chest infiltrates. Sequential abdominal CT and Gallium scans demonstrated a progressive involvement of liver (enlarged liver with multiple nodules), spleen, kidneys, bone marrow and abdomen lymph nodes between 2 weeks and 5 months. An extensive search for other infections turned back negative and a complete immunological work-up was considered normal. At the end of those 5 months, fever vanished and she gradually improved. Chest and abdominal imaging also eventually improved. We concluded from an extensive review of the literature that this case highlights a paradoxical immune mediated reaction similar to the previously described IRIS in HIV infected patients but this time to Mycobacterium Tuberculosis during an appropriate antibiotic treatment. Such an IRIS resulted in an apparent clinical deterioration but turned out not being a failure to treatment. In the future, early recognition of an IRIS in tuberculosis might prevent unnecessary changes in anti-TB regimen.

Targeting FtsZ for Antituberculosis Drug Discovery: Noncytotoxic Taxanes as Novel Antituberculosis Agents

Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.

In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by Helichrysum caespititium

Antimycobacterial activity of acetone and water extracts of Helichrysum caespititium against a drug-sensitive strain of Mycobacterium tuberculosis was evaluated by the agar plate method. The acetone extract exhibited inhibitory activity at a concentration of 0.5mg ml −1 against this strain whereas the organism was found to be partially susceptible to the water extract at 5.0mg ml −1 . The inhibitory activity of the acetone extract was confirmed using the rapid radiometric method and the minimum inhibitory concentration (MIC) was found to be 0.1mg ml −1 . Caespitate, a novel phloroglucinol, which was previously isolated and identified, from H. caespititium was also evaluated for its activity against drugsensitive and drug-resistant strains of M. tuberculosis. The MIC of caespitate was found to be 0.1mg/ml for all the M. tuberculosis strains. The ability of caespitate to inhibit the growth of all the strains of M. tuberculosis, shows the broad spectrum antimycobacterial activity of the compound.

In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by Helichrysum caespititium

In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by Helichrysum caespititium

In vitro inhibition of drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis by ethnobotanically selected South African plants

Twenty South African medicinal plants used to treat pulmonary diseases were screened for activity against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis. A preliminary screening of acetone and water plant extracts against a drug-sensitive strain of Mycobacterium tuberculosis, H37Rv, was done by the agar plate method. Fourteen of the 20 acetone extracts showed inhibitory activity at a concentration of 0.5 mg/ml against this strain. Acetone as well as water extracts of Cryptocarya latifolia, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Thymus vulgaris inhibited the growth of M. tuberculosis. Given the activity of 14 acetone extracts at 0.5 mg/ml against the drug-sensitive strain by the agar plate method, a further study was done employing a rapid radiometric method to confirm the inhibitory activity. These active acetone extracts were screened against the H37Rv strain as well as a strain resistant to the drugs isoniazid and rifampin. The minimal inhibitory concentration of Croton pseudopulchellus, Ekebergia capensis, Euclea natalensis, Nidorella anomala and Polygala myrtifolia was 0.1 mg/ml against the H37Rv strain by the radiometric method. Extracts of Chenopodium ambrosioides, Ekebergia capensis, Euclea natalensis, Helichrysum melanacme, Nidorella anomala and Polygala myrtifolia were active against the resistant strain at 0.1 mg/ml. Eight plants showed activity against both strains at a concentration of 1.0 mg/ml.