2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli
It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 μg/ml. Here, two selected compounds, 2,4-di...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1004632/full |
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| author | M. Korycka-Machała M. Kawka J. Lach R. Płocińska A. Bekier B. Dziadek A. Brzostek P. Płociński P. Płociński D. Strapagiel M. Szczesio K. Gobis J. Dziadek |
| author_facet | M. Korycka-Machała M. Kawka J. Lach R. Płocińska A. Bekier B. Dziadek A. Brzostek P. Płociński P. Płociński D. Strapagiel M. Szczesio K. Gobis J. Dziadek |
| author_sort | M. Korycka-Machała |
| collection | DOAJ |
| description | It was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 μg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR–Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC–MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins. |
| first_indexed | 2024-04-11T17:41:30Z |
| format | Article |
| id | doaj.art-cd94434bc9b94db7ab4d01234764df4b |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T17:41:30Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-cd94434bc9b94db7ab4d01234764df4b2022-12-22T04:11:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-11-011310.3389/fphar.2022.100463210046322,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilliM. Korycka-Machała0M. Kawka1J. Lach2R. Płocińska3A. Bekier4B. Dziadek5A. Brzostek6P. Płociński7P. Płociński8D. Strapagiel9M. Szczesio10K. Gobis11J. Dziadek12Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, PolandDepartment of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandBiobank Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandLaboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, PolandDepartment of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandDepartment of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandLaboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, PolandLaboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, PolandDepartment of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandBiobank Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, PolandInstitute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, PolandDepartment of Organic Chemistry, Medical University of Gdansk, Gdansk, PolandLaboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Lodz, PolandIt was recently reported that 4-substituted picolinohydrazonamides carrying hydrophilic cyclic amines, such as morpholine and pyrrolidine, at the end of their thiosemicarbazide chain have potent antimycobacterial activity in vitro at concentrations below 1 μg/ml. Here, two selected compounds, 2,4-disubstituted pyridine derivatives 11 and 15, revealed significant bactericidal activity against Mycobacterium tuberculosis localized intracellularly within human macrophages, as well as against biofilm-forming tubercle bacilli. Mutants were selected that were resistant to the investigated compounds at an efficiency similar to that identified in the presence of the first line antituberculosis drug rifampicin. The resistant mutants were viable in the presence of the tested compounds exclusively on solid media. Genome-wide sequencing of the mutants selected in the presence of compound 11 revealed the accumulation of nonsynonymous mutations in the mmpR5 gene encoding a transcriptional repressor of the MmpS5-MmpL5 efflux pump, whose upregulation has been associated with bedaquiline resistance. The depletion of MmpR5 in wild-type M. tuberculosis using CRISPR–Cas9 technology increased the resistance of this strain to compound 11. Mass spectrometry-based proteomics (LC–MS/MS) of wild-type tubercle bacilli growing in subinhibitory concentrations of compounds 11 or 15 revealed 15 overproduced proteins not detectable in the control cells, including virulence-related proteins.https://www.frontiersin.org/articles/10.3389/fphar.2022.1004632/fullpyridine derivativestuberculosisdrug resistanceMtb inhibitorsMmpR5biofilm |
| spellingShingle | M. Korycka-Machała M. Kawka J. Lach R. Płocińska A. Bekier B. Dziadek A. Brzostek P. Płociński P. Płociński D. Strapagiel M. Szczesio K. Gobis J. Dziadek 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli Frontiers in Pharmacology pyridine derivatives tuberculosis drug resistance Mtb inhibitors MmpR5 biofilm |
| title | 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli |
| title_full | 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli |
| title_fullStr | 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli |
| title_full_unstemmed | 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli |
| title_short | 2,4-Disubstituted pyridine derivatives are effective against intracellular and biofilm-forming tubercle bacilli |
| title_sort | 2 4 disubstituted pyridine derivatives are effective against intracellular and biofilm forming tubercle bacilli |
| topic | pyridine derivatives tuberculosis drug resistance Mtb inhibitors MmpR5 biofilm |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1004632/full |
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