scholarly journals Bioluminescence screening in vitro (Bio-Siv) assays for high-volume antimycobacterial drug discovery.

1996 ◽  
Vol 40 (6) ◽  
pp. 1536-1541 ◽  
Author(s):  
T M Arain ◽  
A E Resconi ◽  
M J Hickey ◽  
C K Stover
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
High Volume ◽  
Luciferase Gene ◽  
Direct Identification ◽  
Mycobacterium Intracellulare ◽  
Large Numbers ◽  
Antimycobacterial Agents ◽  
Screening In Vitro

Bioluminescence-based assays to indicate antimicrobial susceptibility have been developed and validated for recombinant strains of Mycobacterium tuberculosis, Mycobacterium bovis BCG, Mycobacterium avium, and Mycobacterium intracellulare expressing an integrated eukaryotic luciferase gene. MICs determined with these bioluminescence assays for several antimycobacterial agents, including isoniazid, ethambutol, rifampin, amikacin, streptomycin, ciprofloxacin, and clarithromycin, compared favorably with traditional BACTEC methods and visual estimations of the inhibitory end point. Assay methodology has been optimized for the analysis of large numbers of novel compounds and is simple, inexpensive, and labor efficient. The availability of these four recombinant mycobacteria has permitted a strategy for drug discovery employing the nonpathogenic BCG strain for mass screening purposes with subsequent confirmation of activity against the pathogenic mycobacteria. Furthermore, evidence suggests that the BCG-based screen may allow the direct identification of bactericidal agents.

scholarly journals SYNTHESIS AND ANTITUBERCULAR ACTIVITY OF PIPERIDINE AND MORPHOLINE 1, 8 NAPHTHYRIDINE ANALOGUES

2016 ◽  
Vol 8 (12) ◽  
pp. 252 ◽  
Author(s):  
Muwaffag Badawneh ◽  
Jalal Aljamal
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inhibitory Concentration ◽  
Antitubercular Activity ◽  
Antimycobacterial Activity ◽  
Significant Activity ◽  
Reference Drug ◽  
Novel Drugs ◽  
Elemental Analyses ◽  
Antimycobacterial Agents

<p><strong>Objective: </strong>The search for new, potentially useful antimycobacterial agents. In continuation with our previous screening for the discovery of novel drugs for tuberculosis, a new series of 1,8-naphthyridines derivatives were synthesized and evaluated <em>in vitro </em>for antimycobacterial activity against <em>Mycobacterium tuberculosis </em>H37Rv.</p><p><strong>Methods: </strong>Several 4-morpholinomethyl-1.8-naphthyridine derivatives have been synthesized in excellent yields. The synthesized compounds were characterized by spectroscopic methods as well as elemental analyses. They were screened for their antimycobacterial activity. The growth was monitored radiometrically in 7H12 broth with the BACTEC 460 TB system. The minimum inhibitory concentration (MIC) was determined for compounds that demonstrated ≥ 90% growth inhibition in the primary screening.</p><p><strong>Results: </strong>The obtained data suggested that all compounds showed significant activity against <em>Mycobacterium tuberculosis </em>H37Rv<em> </em>compared to the standard reference drug. Analogues (6-11) having heterocyclic groups in position 7 were the most potent of those we tested.</p><p><strong>Conclusion: </strong>These findings clearly identify the 1,8-naphthyridine analogue (10) with a 6-amino-2-(4'-methoxy benzylamine-4-morpholinomethyl-7-morpholino-substituent as promising anti-tubercular agents possessing significant activity against <em>Mycobacterium tuberculosis </em>H37Rv</p>

scholarly journals Mycobacterium tuberculosis Gyrase Inhibitors as a New Class of Antitubercular Drugs

2015 ◽  
Vol 59 (4) ◽  
pp. 1868-1875 ◽  
Author(s):  
Delia Blanco ◽  
Esther Perez-Herran ◽  
Mónica Cacho ◽  
Lluís Ballell ◽  
Julia Castro ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Oral Absorption ◽  
Cell Activity ◽  
Cross Resistance ◽  
Drug Candidate ◽  
Antibacterial Drug ◽  
Gyrase Inhibitors

ABSTRACTOne way to speed up the TB drug discovery process is to search for antitubercular activity among compound series that already possess some of the key properties needed in anti-infective drug discovery, such as whole-cell activity and oral absorption. Here, we present MGIs, a new series ofMycobacterium tuberculosisgyrase inhibitors, which stem from the long-term efforts GSK has dedicated to the discovery and development of novel bacterial topoisomerase inhibitors (NBTIs). The compounds identified were found to be devoid of fluoroquinolone (FQ) cross-resistance and seem to operate through a mechanism similar to that of the previously described NBTI GSK antibacterial drug candidate. The remarkablein vitroandin vivoantitubercular profiles showed by the hits has prompted us to further advance the MGI project to full lead optimization.

Study on N-(pyridin-4-Yl) Salicylamides as Antimycobacterial Agents

2013 ◽  
Vol 634-638 ◽  
pp. 1371-1375
Author(s):  
Zhi Jun Xin ◽  
Zhong Jia ◽  
Dian He ◽  
Jian Ping Liang ◽  
Lei Tao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Substituent Effect ◽  
Pyridine Ring ◽  
Wide Spectrum ◽  
Minimum Inhibitory Concentrations ◽  
Antimycobacterial Agents

A series of N-(pyridin-4-yl) salicylamides derivatives were prepared through acylation of the corresponding acetylsalicyloyl chlorides with substituted 4-amino-pyridines. These compounds were evaluated in vitro for antimycobacterial activities against Mycobacterium tuberculosis (TB) and Mycobacterium avium (A) by the minimum inhibitory concentrations (MIC) values. Eight of the compounds exhibited lower MIC against A than isoniazide (INH). Meanwhile, four of the compounds exhibited good anti-TB activity, when they were compared with INH. Antimycobacterial activities of N-(pyridin-4-yl) salicylamides were influenced by the balance between hydrophobicity and electron-withdrawing substituent effect on the phenyl and pyridine ring. These studies show that these compounds might serve as prospective wide-spectrum antimycobacterial substances.

The development of tolerance to dodine in Venturia inaequalis

1973 ◽  
Vol 51 (2) ◽  
pp. 379-382 ◽  
Author(s):  
B. H. MacNeill ◽  
Janice Schooley
Keyword(s):  
Venturia Inaequalis ◽  
Spontaneous Mutation ◽  
Free Medium ◽  
Wild Type ◽  
Spontaneous Mutation Rate ◽  
Comparable Level ◽  
Large Numbers ◽  
Screening In Vitro ◽  
Development Of Tolerance

The screening in vitro of large numbers of conidia of Venturia inaequalis against the selection pressure of dodine revealed a spontaneous mutation rate to dodine tolerance of about 1 in 106 conidia screened. Mutants cultured as mycelial disks grew 53–92% as well on a medium containing 0.5 ppm dodine as on a dodine-free medium. A comparable level of tolerance was developed by the wild type after a period of continuous vegetative growth on the dodine medium, but, unlike the mutants, the wild type lost its tolerance when cultured briefly on medium containing no fungicide. One of the seven mutants exhibited the capacity to adapt to increasingly higher concentrations of dodine. It is postulated that the events leading to the development of tolerance to dodine in V. inaequalis may be not only mutational and stable, but also adaptive and reversible, or a combination of both mechanisms.

scholarly journals Rapid Microbiologic and Pharmacologic Evaluation of Experimental Compounds against Mycobacterium tuberculosis

2006 ◽  
Vol 50 (4) ◽  
pp. 1245-1250 ◽  
Author(s):  
Veronica Gruppo ◽  
Christine M. Johnson ◽  
Karen S. Marietta ◽  
Hataichanok Scherman ◽  
Erin E. Zink ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Mouse Serum ◽  
Serum Samples ◽  
Microtiter Plate Assay ◽  
Plate Assay ◽  
Drug Concentrations

ABSTRACT The assessment of physiochemical and pharmacological properties at early stages of drug discovery can accelerate the conversion of hits and leads into candidates for further development. A strategy for streamlined evaluation of compounds against Mycobacterium tuberculosis in the early preclinical stage is presented in this report. As a primary assay to rapidly select experimental compounds with sufficient in vitro activity, the growth inhibition microtiter plate assay was devised as an alternative to current methods. This microdilution plate assay is a liquid culture method based on spectrophotometric readings of the bacillary growth. The performance of this method was compared to the performance of two established susceptibility methods using clinical available tuberculosis (TB) drugs. Data generated from all three assays were similar for all of the tested compounds. A second simple bioassay was devised to assess the oral bioavailability of compounds prior to extensive in vivo efficacy testing. The bioassay estimates drug concentrations in collected serum samples by a microdilution MIC plate method using M. tuberculosis. In the same assay, the MIC of the compound is also determined in the presence of 10% mouse serum as an indication of protein binding. The method was validated using different clinically available TB drugs, and results are discussed in this report. With these methodological advances, screening of compounds against tuberculosis in the preclinical phase will be rapid, can be adapted to semi-high-throughput screening, and will add relevant physicochemical and basic pharmacological criteria to the decision process of drug discovery.

scholarly journals Differential Gene Expression in Response to Exposure to Antimycobacterial Agents and Other Stress Conditions among Seven Mycobacterium tuberculosis whiB-Like Genes

2006 ◽  
Vol 50 (8) ◽  
pp. 2836-2841 ◽  
Author(s):  
Deborah E. Geiman ◽  
Tirumalai R. Raghunand ◽  
Nisheeth Agarwal ◽  
William R. Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Stress Conditions ◽  
Pcr Analysis ◽  
Reverse Transcription Pcr ◽  
Small Proteins ◽  
Antimycobacterial Agents ◽  
Differential Gene ◽  
Biochemical Analyses ◽  
In Vitro Stress

ABSTRACT The seven Mycobacterium tuberculosis whiB-like genes encode small proteins postulated to be transcriptional regulators. A systematic real-time reverse transcription-PCR analysis following exposure to antibiotics and a variety of growth and in vitro stress conditions indicates differential, and in some cases dramatic, transcription modulations for the different M. tuberculosis whiB family members. This information together with biochemical analyses of the whiB1 to whiB7 gene products will be important for understanding the biology of this novel family of proteins in mycobacteria and related actinomycetes.

scholarly journals Comparative antimycobacterial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations.

1996 ◽  
Vol 40 (11) ◽  
pp. 2655-2657 ◽  
Author(s):  
S L Moghazeh ◽  
X Pan ◽  
T Arain ◽  
C K Stover ◽  
J M Musser ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Rna Polymerase ◽  
Gene Mutations ◽  
Rpob Gene ◽  
Genetic Alterations ◽  
Beta Subunit ◽  
Polymerase Beta ◽  
Antimycobacterial Agents ◽  
Rifampin Resistance

A collection of 24 rifampin-resistant clinical isolates of Mycobacterium tuberculosis with characterized RNA polymerase beta-subunit (rpoB) gene mutations was tested against the antimycobacterial agents rifampin, rifapentine, and KRM-1648 to correlate levels of resistance with specific rpoB genotypes. The results indicate that KRM-1648 is more active in vitro than rifampin and rifapentine, and its ability to overcome rifampin resistance in strains with four different genetic alterations may prove to be useful in understanding structure-function relationships.

scholarly journals Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Yumi Park ◽  
Yong-Mo Ahn ◽  
Surendranadha Jonnala ◽  
Sangmi Oh ◽  
Julia M. Fisher ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Macrophage Infection ◽  
Content Type ◽  
Magnesium Homeostasis ◽  
Direct Binding ◽  
Pore Opening

ABSTRACT Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg2+/Co2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating conditions in vitro and were efficacious against the organism during macrophage infection. However, the compound lacked efficacy in infected mice, possibly due to limited exposure. Our results indicate that inhibition of Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

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