scholarly journals In VitroCombination Studies of Benzothiazinone Lead Compound BTZ043 against Mycobacterium tuberculosis

2012 ◽  
Vol 56 (11) ◽  
pp. 5790-5793 ◽  
Author(s):  
Benoit Lechartier ◽  
Ruben C. Hartkoorn ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Bactericidal Effect ◽  
Lead Compound ◽  
Content Type ◽  
Drug Candidates ◽  
New Class ◽  
Novel Targets ◽  
Essential Enzyme ◽  
Strain H37rv

ABSTRACTBenzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates againstMycobacterium tuberculosisstrain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect onM. tuberculosisthan TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ-resistantM. tuberculosismutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen.

scholarly journals A Novel 6-Benzyl Ether Benzoxaborole Is Active against Mycobacterium tuberculosisIn Vitro

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Nipul Patel ◽  
Theresa O'Malley ◽  
Yong-Kang Zhang ◽  
Yi Xia ◽  
Bjorn Sunde ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Liquid Medium ◽  
Inhibitory Concentration ◽  
Solid Medium ◽  
Eukaryotic Cells ◽  
Intracellular Bacteria ◽  
Benzyl Ether ◽  
Content Type ◽  
Resistant Mutants

ABSTRACT We identified a novel 6-benzyl ether benzoxaborole with potent activity against Mycobacterium tuberculosis. The compound had an MIC of 2 μM in liquid medium. The compound was also able to prevent growth on solid medium at 0.8 μM and was active against intracellular bacteria (50% inhibitory concentration [IC50] = 3.6 μM) without cytotoxicity against eukaryotic cells (IC50 > 100 μM). We isolated resistant mutants (MIC ≥ 100 μM), which had mutations in Rv1683, Rv3068c, and Rv0047c.

scholarly journals Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Seong Won Choi ◽  
Yuexi Gu ◽  
Ryan Scott Peters ◽  
Padmini Salgame ◽  
Jerrold J. Ellner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Lead Compound ◽  
Content Type ◽  
Tuberculosis Model

ABSTRACT Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at Mycobacterium tuberculosis. Ambroxol, a lead compound, emerged from a screen for autophagy-inducing drugs. At clinically relevant doses, ambroxol induced autophagy in vitro and in vivo and promoted mycobacterial killing in macrophages. Ambroxol also potentiated rifampin activity in a murine tuberculosis model.

scholarly journals Correlates between Models of Virulence for Mycobacterium tuberculosis among Isolates of the Central Asian Lineage: a Case for Lysozyme Resistance Testing?

2015 ◽  
Vol 83 (6) ◽  
pp. 2213-2223 ◽  
Author(s):  
Claire Pardieu ◽  
Nicola Casali ◽  
Simon O. Clark ◽  
Richard Hooper ◽  
Ann Williams ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Ex Vivo ◽  
Resistance Testing ◽  
Snp Analysis ◽  
Single Nucleotide ◽  
Content Type ◽  
Differential Outcomes ◽  
Central Asian ◽  
Strain H37rv

Virulence factors (VFs) contribute to the emergence of new humanMycobacterium tuberculosisstrains, are lineage dependent, and are relevant to the development ofM. tuberculosisdrugs/vaccines. VFs were sought withinM. tuberculosislineage 3, which has the Central Asian (CAS) spoligotype. Three isolates were selected from clusters previously identified as dominant in London, United Kingdom. Strain-associated virulence was studied in guinea pig, monocyte-derived macrophage, and lysozyme resistance assays. Whole-genome sequencing, single nucleotide polymorphism (SNP) analysis, and a literature review contributed to the identification of SNPs of interest. The animal model revealed borderline differences in strain-associated pathogenicity.Ex vivo, isolate C72 exhibited statistically significant differences in intracellular growth relative to C6 and C14. SNP candidates inducing lower fitness levels included 123 unique nonsynonymous SNPs, including three located in genes (lysX,caeA, andponA2) previously identified as VFs in the laboratory-adapted reference strain H37Rv and shown to confer lysozyme resistance. C72 growth was most affected by lysozymein vitro. A BLAST search revealed that all three SNPs of interest (C35F, P76Q, and P780R) also occurred in Tiruvallur, India, and in Uganda. Unlike C72, however, no single isolate identified through BLAST carried all three SNPs simultaneously. CAS isolates representative of three medium-sized human clusters demonstrated differential outcomes in models commonly used to estimate strain-associated virulence, supporting the idea that virulence varies within, not just across,M. tuberculosislineages. Three VF SNPs of interest were identified in two additional locations worldwide, which suggested independent selection and supported a role for these SNPs in virulence. The relevance of lysozyme resistance to strain virulence remains to be established.

scholarly journals Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis

2014 ◽  
Vol 58 (12) ◽  
pp. 7557-7559 ◽  
Author(s):  
L. Davies Forsman ◽  
T. Schön ◽  
U. S. H. Simonsson ◽  
J. Bruchfeld ◽  
M. Larsson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Option ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Potential Treatment ◽  
Time Curve ◽  
Content Type ◽  
Extensively Drug Resistant ◽  
Concentration Time ◽  
Strain H37rv

ABSTRACTWe investigated the activity of trimethoprim-sulfamethoxazole (SXT) againstMycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0–24/MIC) using ≥25 as a potential target, the cumulative fraction response was ≥90% at doses of ≥2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

scholarly journals In VitroandIn VivoActivities of Three Oxazolidinones against Nonreplicating Mycobacterium tuberculosis

2014 ◽  
Vol 58 (6) ◽  
pp. 3217-3223 ◽  
Author(s):  
Ming Zhang ◽  
Claudia Sala ◽  
Neeraj Dhar ◽  
Anthony Vocat ◽  
Vasan K Sambandamurthy ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Latent Tuberculosis ◽  
Drug Susceptibility ◽  
New Combination ◽  
Drug Candidate ◽  
Bacteriostatic Effect ◽  
Content Type ◽  
New Class ◽  
Modest Activity

ABSTRACTOxazolidinones represent a new class of antituberculosis drugs that exert their function by inhibiting protein synthesis. Here, we compared the activities of three oxazolidinones, linezolid, PNU-100480, and AZD5847, against latent tuberculosis using a simple model employing the streptomycin-starvedMycobacterium tuberculosisstrain 18b. Thein vitrodrug susceptibility results showed that the three oxazolidinones had a bacteriostatic effect against actively growing bacilli but potent bactericidal activity against nonreplicating cells. In the murine model of latent infection withM. tuberculosis18b, the efficacy of the three compounds varied greatly. Indeed, AZD5847 or its prodrug exhibited no activity or only modest activity, respectively, after 2 months of treatment, whereas both linezolid and PNU-100480 were effective against latent bacilli in mice and showed promising outcomes in combination therapy with rifampin. Moreover, the potency of PNU-100480 was significantly greater than that of linezolid, making it an attractive drug candidate in the development of new combination therapies for latent tuberculosis.

scholarly journals Triazole-Based Compound as a Candidate To Develop Novel Medicines To Treat Toxoplasmosis

2014 ◽  
Vol 58 (12) ◽  
pp. 7583-7585 ◽  
Author(s):  
Katarzyna Dzitko ◽  
Agata Paneth ◽  
Tomasz Plech ◽  
Jakub Pawełczyk ◽  
Lidia Węglińska ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Purine Nucleoside Phosphorylase ◽  
Inhibitory Concentration ◽  
Chemotherapeutic Agent ◽  
Host Cells ◽  
Purine Nucleoside ◽  
Content Type ◽  
New Class ◽  
Future Work ◽  
Better Than

ABSTRACTThis article reports anti-Toxoplasma gondiiactivity of 3-(thiophen-2-yl)-1,2,4-triazole-5-thione. The compound displayed significant and reproducible antiparasitic effects at nontoxic concentrations for the host cells, with an experimentally determined 50% inhibitory concentration (IC50) at least 30 times better than that of the known chemotherapeutic agent sulfadiazine. Purine nucleoside phosphorylase was defined as the probable target for anti-Toxoplasmaactivity of the tested compound. These results provide the foundation for future work to develop a new class of medicines to better treat toxoplasmosis.

scholarly journals The New Pyrazolyltetrazole Derivative MSN20 Is Effective via Oral Delivery against Cutaneous Leishmaniasis

2014 ◽  
Vol 58 (10) ◽  
pp. 6290-6293 ◽  
Author(s):  
Viviane dos Santos Faiões ◽  
Maurício Silva dos Santos ◽  
Alice Maria Rolim Bernardino ◽  
Edézio Ferreira Cunha-Júnior ◽  
Marilene Marcuzzo do Canto Cavalheiro ◽  
...  
Keyword(s):  
Effective Treatment ◽  
Cutaneous Leishmaniasis ◽  
Oral Delivery ◽  
Inhibitory Concentration ◽  
Oral Treatment ◽  
Parasite Load ◽  
Leishmania Amazonensis ◽  
Lead Compound ◽  
Content Type ◽  
Medical Need

ABSTRACTAn orally delivered, safe and effective treatment for leishmaniasis is an unmet medical need. Azoles and the pyrazolylpyrimidine allopurinol present leishmanicidal activity, but their clinical efficacies are variable. Here, we describe the activity of the new pyrazolyltetrazole hybrid, 5-[5-amino-1-(4′-methoxyphenyl)1H-pyrazole-4-yl]1H-tetrazole (MSN20). MSN20 showed a 50% inhibitory concentration (IC50) of 22.3 μM against amastigotes ofLeishmania amazonensisand reduced significantly the parasite load in infected mice, suggesting its utility as a lead compound for the development of an oral treatment for leishmaniasis.

scholarly journals Genome Sequences of the Mycobacterium tuberculosis H37Rv-ptkA Deletion Mutant and Its Parental Strain

2017 ◽  
Vol 5 (44) ◽  
Author(s):  
Clement K. M. Tsui ◽  
Dennis Wong ◽  
Gagandeep Narula ◽  
Jennifer L. Gardy ◽  
William W. H. Hsiao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Parental Strain ◽  
Deletion Mutant ◽  
Protein Tyrosine Kinase ◽  
Draft Genome ◽  
Genome Sequences ◽  
Genetic Studies ◽  
Content Type ◽  
Mycobacterium Tuberculosis H37rv ◽  
Strain H37rv

ABSTRACT Mycobacterium tuberculosis, the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Here, we report the draft genome sequences of the M. tuberculosis protein tyrosine kinase (ptkA) deletion mutant and its parental strain H37Rv, which are used in genetic studies and for drug discovery.

scholarly journals Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates

2012 ◽  
Vol 56 (5) ◽  
pp. 2643-2651 ◽  
Author(s):  
Meenakshi Balganesh ◽  
Neela Dinesh ◽  
Sreevalli Sharma ◽  
Sanjana Kuruppath ◽  
Anju V. Nair ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Vital Role ◽  
Major Facilitator Superfamily ◽  
Content Type ◽  
Active Efflux ◽  
Drug Candidates ◽  
Small Multidrug Resistance ◽  
Major Facilitator

ABSTRACTActive efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms inMycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil andl-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded byRv1218c, and the SMR (small multidrug resistance) class, encoded byRv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded byRv0849andRv1258calso mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WTM. tuberculosiscells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps ofM. tuberculosisplay a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization ofRv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

scholarly journals ANTI-MYCOBACTERIUM TUBERCULOSIS STRAIN H37RV AND IRON CHELATION ACTIVITY OF SAPPAN WOOD EXTRACT (CAESALPINIA SAPPAN L.) IN VITRO

2018 ◽  
Vol 11 (6) ◽  
pp. 444
Author(s):  
Ratu Safitri ◽  
Ida Indrawati ◽  
Mas Rizky A A Syamsunarno ◽  
Mohammad Ghozali ◽  
Basri A Gani ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Minimum Bactericidal Concentration ◽  
Iron Chelation ◽  
Iron Chelate ◽  
Caesalpinia Sappan ◽  
Lowenstein Jensen ◽  
Wood Extract ◽  
Strain H37rv

Objective: The objective of this study is to determine anti-Mycobacterium tuberculosis (MTB) strain H37Rv and iron chelation activities of sappan wood extract (SWE).Methods: The evaluation of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) by proportion methods. Whereas the iron chelate in Lowenstein–Jensen (LJ) medium as the indicator of Mycobacterium growth and SWE effect.Results: The SWE has bacteriocidal to MTB of 10−3 and 10−5 dilutions in of all concentrations (250, 500, 750, 1000, 2000, 4000, 8000, and 16000 part per millions [ppm]) also bacteriostatic in concentration 50 and 100 ppm.Conclusion: The SWE at 100 ppm could inhibit 87% of the MTB in 10−3 and 10−5 dilutions, respectively, also to reduce to growth the colony of MTB, and has chelating effects of iron expression of LJ medium and MTB.

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