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Article ; Online: InhA inhibitors have activity against non-replicating Mycobacterium tuberculosis.

Flint, Lindsay / Korkegian, Aaron / Parish, Tanya

PloS one

2020 Volume 15, Issue 11, Page(s) e0239354

Abstract: We previously identified a diazaborine series with potential for development as a new tuberculosis drug. This series has activity in vitro and in vivo and targets cell wall biosynthesis via inhibition of InhA. The overall aim of this study was to ... ...

Abstract	We previously identified a diazaborine series with potential for development as a new tuberculosis drug. This series has activity in vitro and in vivo and targets cell wall biosynthesis via inhibition of InhA. The overall aim of this study was to determine whether InhA inhibitors have activity against non-replicating Mycobacterium tuberculosis. We tested the ability of two molecules of the diazaborine series to kill non-replicating M. tuberculosis in the nutrient starvation model; both molecules were bactericidal, reducing viability by >3 logs in 21 days. Activity showed similar kill rates to other InhA inhibitors (isoniazid and NITD-916). We conclude that inhibition of InhA is bactericidal against nutrient-starved non-replicating M. tuberculosis.
MeSH term(s)	Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Inhibins/antagonists & inhibitors ; Microbial Sensitivity Tests/methods ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/metabolism
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; inhibin-alpha subunit ; Inhibins (57285-09-3)
Language	English
Publishing date	2020-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0239354
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Article ; Online: Identification of 2-Amino Benzothiazoles with Bactericidal Activity against Mycobacterium tuberculosis.

Bonnett, Shilah / Jee, Jo-Ann / Chettiar, Somsundaram / Ovechkina, Yulia / Korkegian, Aaron / Greve, Eric / Odingo, Joshua / Parish, Tanya

Microbiology spectrum

2023 Volume 11, Issue 1, Page(s) e0497422

Abstract: We identified an amino-benzothiazole scaffold from a whole-cell screen against recombinant Mycobacterium tuberculosis under expressing the essential signal peptidase LepB. The seed molecule had 2-fold higher activity against the LepB hypomorph. Through a ...

Abstract	We identified an amino-benzothiazole scaffold from a whole-cell screen against recombinant Mycobacterium tuberculosis under expressing the essential signal peptidase LepB. The seed molecule had 2-fold higher activity against the LepB hypomorph. Through a combination of purchase and chemical synthesis, we explored the structure-activity relationship for this series; 34 analogs were tested for antitubercular activity and for cytotoxicity against eukaryotic cells. We identified molecules with improved potency and reduced cytotoxicity. However, molecules did not appear to target LepB directly and did not inhibit protein secretion. Key compounds showed good permeability, low protein binding, and lack of CYP inhibition, but metabolic stability was poor with short half-lives. The seed molecule showed good bactericidal activity against both replicating and nonreplicating bacteria, as well as potency against intracellular M. tuberculosis in murine macrophages. Overall, the microbiological properties of the series are attractive if metabolic stability can be improved, and identification of the target could assist in the development of this series.
MeSH term(s)	Animals ; Mice ; Mycobacterium tuberculosis/metabolism ; Antitubercular Agents/pharmacology ; Antitubercular Agents/chemistry ; Tuberculosis/drug therapy ; Tuberculosis/microbiology ; Structure-Activity Relationship ; Protein Binding ; Microbial Sensitivity Tests
Chemical Substances	Antitubercular Agents
Language	English
Publishing date	2023-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.04974-22
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Article ; Online: Triazolopyrimidines Target Aerobic Respiration in Mycobacterium tuberculosis.

Shelton, Catherine / McNeil, Matthew / Allen, Renee / Flint, Lindsay / Russell, Dara / Berube, Bryan / Korkegian, Aaron / Ovechkina, Yulia / Parish, Tanya

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 4, Page(s) e0204121

Abstract: We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a subunit of the ... ...

Abstract	We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a subunit of the cytochrome
MeSH term(s)	Antitubercular Agents/pharmacology ; Cytochromes ; Electron Transport Complex IV/genetics ; Electron Transport Complex IV/metabolism ; Humans ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Respiration
Chemical Substances	Antitubercular Agents ; Cytochromes ; Electron Transport Complex IV (EC 1.9.3.1)
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.02041-21
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Article ; Online: Corrigendum to "Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA" [Tuberculosis 107 (December 2017) 133-136].

McNeil, Matthew B / Dennison, Devon / Shelton, Catherine / Flint, Lindsay / Korkegian, Aaron / Parish, Tanya

Tuberculosis (Edinburgh, Scotland)

2018 Volume 110, Page(s) 123

Language	English
Publishing date	2018-02-21
Publishing country	Scotland
Document type	Journal Article ; Published Erratum
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2018.02.001
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Article ; Online: Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening.

Kumar, Anuradha / Chettiar, Somsundaram / Brown, Brian S / Early, Julie / Ollinger, Juliane / Files, Megan / Bailey, Mai A / Korkegian, Aaron / Dennison, Devon / McNeil, Matthew / Metz, James / Osuma, Augustine / Curtin, Michael / Kunzer, Aaron / Freiberg, Gail / Bruncko, Milan / Kempf, Dale / Parish, Tanya

Scientific reports

2022 Volume 12, Issue 1, Page(s) 14879

Abstract: We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular ... ...

Abstract	We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure-activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series.
MeSH term(s)	Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Bacterial Proteins/metabolism ; High-Throughput Screening Assays ; Membrane Transport Proteins/genetics ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/metabolism
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Membrane Transport Proteins
Language	English
Publishing date	2022-09-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-19192-7
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Article ; Online: Design, synthesis and SAR of antitubercular benzylpiperazine ureas.

Satish, Sohal / Chitral, Rohan / Kori, Amitkumar / Sharma, Basantkumar / Puttur, Jayashree / Khan, Afreen A / Desle, Deepali / Raikuvar, Kavita / Korkegian, Aaron / Martis, Elvis A F / Iyer, Krishna R / Coutinho, Evans C / Parish, Tanya / Nandan, Santosh

Molecular diversity

2021 Volume 26, Issue 1, Page(s) 73–96

Abstract: N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to ... ...

Abstract	N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC
MeSH term(s)	Antitubercular Agents/pharmacology ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Molecular Structure ; Mycobacterium tuberculosis ; Piperazines/pharmacology ; Structure-Activity Relationship ; Urea/pharmacology
Chemical Substances	Antitubercular Agents ; Piperazines ; Urea (8W8T17847W)
Language	English
Publishing date	2021-01-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1376507-3
ISSN	1573-501X ; 1381-1991
ISSN (online)	1573-501X
ISSN	1381-1991
DOI	10.1007/s11030-020-10158-3
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Article ; Online: Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA.

McNeil, Matthew B / Dennison, Devon / Shelton, Catherine / Flint, Lindsay / Korkegian, Aaron / Parish, Tanya

Tuberculosis (Edinburgh, Scotland)

2017 Volume 107, Page(s) 133–136

Abstract: Isoniazid inhibits Mycobacterium tuberculosis InhA and is a key component of drug regimens that treat tuberculosis. However, the high rate of resistance against isoniazid is a contributing factor to the emergence of multi-drug resistance strains of M. ... ...

Abstract	Isoniazid inhibits Mycobacterium tuberculosis InhA and is a key component of drug regimens that treat tuberculosis. However, the high rate of resistance against isoniazid is a contributing factor to the emergence of multi-drug resistance strains of M. tuberculosis. The 4-hydroxy-2-pyridine NITD-916 is a direct inhibitor of M. tuberculosis InhA that has comparable efficacy to isoniazid in mouse models of TB infection but a lower frequency of resistance. To characterize resistance mechanisms against NITD-916 we isolated resistant mutants in H37Rv (Euro-American lineage) and HN878 (East-Asian lineage) strains of M. tuberculosis. The resistance frequency was similar in both strains. Mutations were identified in residues within or near to the active of InhA or in the fabG1inhA promoter region. All mutants were resistant to NITD-916 but were not cross resistant to isoniazid, despite homology to SNPs identified in isoniazid resistant clinical isolates.
MeSH term(s)	Antitubercular Agents/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Drug Resistance, Bacterial/genetics ; Genotype ; Isoniazid/pharmacology ; Microbial Sensitivity Tests ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/genetics ; Oxidoreductases/antagonists & inhibitors ; Oxidoreductases/genetics ; Oxidoreductases/metabolism ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Pyridines/pharmacology
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Pyridines ; 2,4-dihydroxypyridine (626-03-9) ; Oxidoreductases (EC 1.-) ; InhA protein, Mycobacterium (EC 1.3.1.9) ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2017-09-13
Publishing country	Scotland
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2017.09.003
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Article ; Online: Mutations in the essential arabinosyltransferase EmbC lead to alterations in Mycobacterium tuberculosis lipoarabinomannan.

Korkegian, Aaron / Roberts, David M / Blair, Rachel / Parish, Tanya

The Journal of biological chemistry

2014 Volume 289, Issue 51, Page(s) 35172–35181

Abstract: The Mycobacterium tuberculosis cell wall is a complex structure essential for the viability of the organism and its interaction with the host. The glycolipid lipoarabinomannan (LAM) plays an important role in mediating host-bacteria interactions and is ... ...

Abstract	The Mycobacterium tuberculosis cell wall is a complex structure essential for the viability of the organism and its interaction with the host. The glycolipid lipoarabinomannan (LAM) plays an important role in mediating host-bacteria interactions and is involved in modulation of the immune response. The arabinosyltransferase EmbC required for LAM biosynthesis is essential. We constructed recombinant strains of M. tuberculosis expressing a variety of alleles of EmbC. We demonstrated that EmbC has a functional signal peptide in M. tuberculosis. Over- or underexpression of EmbC resulted in reduced or increased sensitivity to ethambutol, respectively. The C-terminal domain of EmbC was essential for activity because truncated alleles were unable to mediate LAM production in Mycobacterium smegmatis and were unable to complement an embC deletion in M. tuberculosis. The C-terminal domain of the closely related arabinosyltransferase EmbB was unable to complement the function of the EmbC C-terminal domain. Two functional motifs were identified. The GT-C motif contains two aspartate residues essential for function in the DDX motif. The proline-rich region contains two highly conserved asparagines (Asn-638 and Asn-652). Mutation of these residues was tolerated, but loss of Asn-638 resulted in the synthesis of truncated LAM, which appeared to lack arabinose branching. All embC alleles that were incapable of complementing LAM production in M. smegmatis were not viable in M. tuberculosis, supporting the hypothesis that LAM itself is essential in M. tuberculosis.
MeSH term(s)	Amino Acid Sequence ; Antitubercular Agents/pharmacology ; Asparagine/genetics ; Asparagine/metabolism ; Aspartic Acid/genetics ; Aspartic Acid/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Blotting, Western ; Ethambutol/pharmacology ; Gene Expression Regulation, Bacterial ; Genes, Essential/genetics ; Lipopolysaccharides/biosynthesis ; Microbial Viability/genetics ; Molecular Sequence Data ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Pentosyltransferases/chemistry ; Pentosyltransferases/genetics ; Pentosyltransferases/metabolism ; Protein Sorting Signals/genetics ; Protein Structure, Secondary ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Homology, Amino Acid
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Lipopolysaccharides ; Protein Sorting Signals ; lipoarabinomannan ; Aspartic Acid (30KYC7MIAI) ; Asparagine (7006-34-0) ; Ethambutol (8G167061QZ) ; Pentosyltransferases (EC 2.4.2.-) ; arabinosyltransferase (EC 2.4.2.-)
Language	English
Publishing date	2014-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M114.583112
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Article: Novel Trifluoromethyl Pyrimidinone Compounds With Activity Against

Hembre, Erik / Early, Julie V / Odingo, Joshua / Shelton, Catherine / Anoshchenko, Olena / Guzman, Junitta / Flint, Lindsay / Dennison, Devon / McNeil, Matthew B / Korkegian, Aaron / Ovechkina, Yulia / Ornstein, Paul / Masquelin, Thierry / Hipskind, Philip A / Parish, Tanya

Frontiers in chemistry

2021 Volume 9, Page(s) 613349

Abstract: The identification and development of new anti-tubercular agents are a priority research area. We identified the trifluoromethyl pyrimidinone series of compounds in a whole-cell screen ... ...

Abstract	The identification and development of new anti-tubercular agents are a priority research area. We identified the trifluoromethyl pyrimidinone series of compounds in a whole-cell screen against
Language	English
Publishing date	2021-04-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2021.613349
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Article ; Online: 8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis.

Odingo, Joshua O / Early, Julie V / Smith, Jake / Johnson, James / Bailey, Mai A / Files, Megan / Guzman, Junitta / Ollinger, Juliane / Korkegian, Aaron / Kumar, Anuradha / Ovechkina, Yulia / Parish, Tanya

Drug development research

2019 Volume 80, Issue 5, Page(s) 566–572

Abstract: There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a ...

Abstract	There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8-hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure-activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8-hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub-family of 2-styryl-substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC
MeSH term(s)	Animals ; Antitubercular Agents/chemical synthesis ; Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Chlorocebus aethiops ; Hep G2 Cells ; Humans ; Hydroxyquinolines/chemical synthesis ; Hydroxyquinolines/chemistry ; Hydroxyquinolines/pharmacology ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Molecular Structure ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/growth & development ; Oxyquinoline/analogs & derivatives ; Structure-Activity Relationship ; Vero Cells
Chemical Substances	Antitubercular Agents ; Hydroxyquinolines ; Oxyquinoline (5UTX5635HP)
Language	English
Publishing date	2019-03-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604587-x
ISSN	1098-2299 ; 0272-4391
ISSN (online)	1098-2299
ISSN	0272-4391
DOI	10.1002/ddr.21531
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