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Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain
Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed. The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitor...
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Published in: | Memórias do Instituto Oswaldo Cruz 2023, Vol.118, p.e230143-e230143 |
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creator | Rodríguez-Carlos, Adrián Jacobo-Delgado, Yolanda Santos-Mena, Alan Orlando García-Hernández, Mariana H De Jesus-Gonzalez, Luis Adrian Lara-Ramirez, Edgar E Rivas-Santiago, Bruno |
description | Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed.
The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity.
Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis.
Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB. |
doi_str_mv | 10.1590/0074-02760230143 |
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The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity.
Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis.
Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.</description><identifier>ISSN: 0074-0276</identifier><identifier>ISSN: 1678-8060</identifier><identifier>EISSN: 1678-8060</identifier><identifier>DOI: 10.1590/0074-02760230143</identifier><identifier>PMID: 38126492</identifier><language>eng</language><publisher>Brazil: Instituto Oswaldo Cruz, Ministério da Saúde</publisher><subject>Antitubercular Agents - pharmacology ; Antitubercular Agents - therapeutic use ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylase Inhibitors - therapeutic use ; Histone Deacetylases ; Humans ; Mycobacterium tuberculosis ; PARASITOLOGY ; Rifampin - pharmacology ; TROPICAL MEDICINE ; Tuberculosis - drug therapy ; Tuberculosis - microbiology ; Tuberculosis, Multidrug-Resistant - drug therapy</subject><ispartof>Memórias do Instituto Oswaldo Cruz, 2023, Vol.118, p.e230143-e230143</ispartof><rights>This work is licensed under a Creative Commons Attribution 4.0 International License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3183-4ac7709d6ad66b02825eb92352e8c380169feae1e23638af546091540b62c04c3</cites><orcidid>0000-0002-1521-1519</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,4024,24150,27923,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38126492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rodríguez-Carlos, Adrián</creatorcontrib><creatorcontrib>Jacobo-Delgado, Yolanda</creatorcontrib><creatorcontrib>Santos-Mena, Alan Orlando</creatorcontrib><creatorcontrib>García-Hernández, Mariana H</creatorcontrib><creatorcontrib>De Jesus-Gonzalez, Luis Adrian</creatorcontrib><creatorcontrib>Lara-Ramirez, Edgar E</creatorcontrib><creatorcontrib>Rivas-Santiago, Bruno</creatorcontrib><title>Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain</title><title>Memórias do Instituto Oswaldo Cruz</title><addtitle>Mem Inst Oswaldo Cruz</addtitle><description>Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed.
The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity.
Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis.
Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.</description><subject>Antitubercular Agents - pharmacology</subject><subject>Antitubercular Agents - therapeutic use</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylase Inhibitors - therapeutic use</subject><subject>Histone Deacetylases</subject><subject>Humans</subject><subject>Mycobacterium tuberculosis</subject><subject>PARASITOLOGY</subject><subject>Rifampin - pharmacology</subject><subject>TROPICAL MEDICINE</subject><subject>Tuberculosis - drug therapy</subject><subject>Tuberculosis - microbiology</subject><subject>Tuberculosis, Multidrug-Resistant - drug therapy</subject><issn>0074-0276</issn><issn>1678-8060</issn><issn>1678-8060</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNo9kUtv3CAUhVHVqJmm3XdVsUwXTi4PY3sZTdJOpUSV-lgjjK8bIhumgCvNT8q_DNOZzgoE5zsXziHkA4MrVndwDdDICnijgAtgUrwiK6aatmpBwWuyOl2fk7cpPUHZCiXfkHPRMq5kx1fkeeNSDh7pgMZi3k0mIb3c3N6sP1HnH13vcoipon05H-gQl9-JmogUxxFtdn-R5kBt8DmGiT7sbOiNzRjdMtO89BjtMoXkUvH6pw-eGj_QbQxzyIV9RJrQpzJmcnlHxxBpdKOZt846XyD6cPudphyN8-_I2WimhO-P6wX59fnu53pT3X_78nV9c19ZwVpRSWObBrpBmUGpHnjLa-w7LmqOrRUtMNWNaJAhF0q0Zqylgo7VEnrFLUgrLsjVwTdZh1PQT2GJvgzUP_Zx6n2cfB83AAPGhCzA5QEov_qzYMp6dsniNBmPYUmadyDrpjxAFCkcpDaGlCKOehvdbOJOM9D7RvVpxrHRgnw8ui_9jMMJ-F-heAH7spqW</recordid><startdate>2023</startdate><enddate>2023</enddate><creator>Rodríguez-Carlos, Adrián</creator><creator>Jacobo-Delgado, Yolanda</creator><creator>Santos-Mena, Alan Orlando</creator><creator>García-Hernández, Mariana H</creator><creator>De Jesus-Gonzalez, Luis Adrian</creator><creator>Lara-Ramirez, Edgar E</creator><creator>Rivas-Santiago, Bruno</creator><general>Instituto Oswaldo Cruz, Ministério da Saúde</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>GPN</scope><orcidid>https://orcid.org/0000-0002-1521-1519</orcidid></search><sort><creationdate>2023</creationdate><title>Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain</title><author>Rodríguez-Carlos, Adrián ; Jacobo-Delgado, Yolanda ; Santos-Mena, Alan Orlando ; García-Hernández, Mariana H ; De Jesus-Gonzalez, Luis Adrian ; Lara-Ramirez, Edgar E ; Rivas-Santiago, Bruno</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3183-4ac7709d6ad66b02825eb92352e8c380169feae1e23638af546091540b62c04c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antitubercular Agents - pharmacology</topic><topic>Antitubercular Agents - therapeutic use</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylase Inhibitors - therapeutic use</topic><topic>Histone Deacetylases</topic><topic>Humans</topic><topic>Mycobacterium tuberculosis</topic><topic>PARASITOLOGY</topic><topic>Rifampin - pharmacology</topic><topic>TROPICAL MEDICINE</topic><topic>Tuberculosis - drug therapy</topic><topic>Tuberculosis - microbiology</topic><topic>Tuberculosis, Multidrug-Resistant - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rodríguez-Carlos, Adrián</creatorcontrib><creatorcontrib>Jacobo-Delgado, Yolanda</creatorcontrib><creatorcontrib>Santos-Mena, Alan Orlando</creatorcontrib><creatorcontrib>García-Hernández, Mariana H</creatorcontrib><creatorcontrib>De Jesus-Gonzalez, Luis Adrian</creatorcontrib><creatorcontrib>Lara-Ramirez, Edgar E</creatorcontrib><creatorcontrib>Rivas-Santiago, Bruno</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SciELO</collection><jtitle>Memórias do Instituto Oswaldo Cruz</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rodríguez-Carlos, Adrián</au><au>Jacobo-Delgado, Yolanda</au><au>Santos-Mena, Alan Orlando</au><au>García-Hernández, Mariana H</au><au>De Jesus-Gonzalez, Luis Adrian</au><au>Lara-Ramirez, Edgar E</au><au>Rivas-Santiago, Bruno</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain</atitle><jtitle>Memórias do Instituto Oswaldo Cruz</jtitle><addtitle>Mem Inst Oswaldo Cruz</addtitle><date>2023</date><risdate>2023</risdate><volume>118</volume><spage>e230143</spage><epage>e230143</epage><pages>e230143-e230143</pages><issn>0074-0276</issn><issn>1678-8060</issn><eissn>1678-8060</eissn><abstract>Tuberculosis (TB) is a major public health problem, which has been aggravated by the alarming growth of drug-resistant tuberculosis. Therefore, the development of a safer and more effective treatment is needed.
The aim of this work was repositioning and evaluate histone deacetylases (HDAC) inhibitors- based drugs with potential antimycobacterial activity.
Using an in silico pharmacological repositioning strategy, three molecules that bind to the catalytic site of histone deacetylase were selected. Pneumocytes type II and macrophages were infected with Mycobacterium tuberculosis and treated with pre-selected HDAC inhibitors (HDACi). Subsequently, the ability of each of these molecules to directly promote the elimination of M. tuberculosis was evaluated by colony-forming unit (CFU)/mL. We assessed the expression of antimicrobial peptides and respiratory burst using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Aminoacetanilide (ACE), N-Boc-1,2-phenylenediamine (N-BOC), 1,3-Diphenylurea (DFU), reduce bacillary loads in macrophages and increase the production of β-defensin-2, LL-37, superoxide dismutase (SOD) 3 and inducible nitric oxide synthase (iNOS). While only the use of ACE in type II pneumocytes decreases the bacterial load through increasing LL-37 expression. Furthermore, the use of ACE and rifampicin inhibited the survival of intracellular multi-drug resistance M. tuberculosis.
Our data support the usefulness of in silico approaches for drug repositioning to provide a potential adjunctive therapy for TB.</abstract><cop>Brazil</cop><pub>Instituto Oswaldo Cruz, Ministério da Saúde</pub><pmid>38126492</pmid><doi>10.1590/0074-02760230143</doi><orcidid>https://orcid.org/0000-0002-1521-1519</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Antitubercular Agents - pharmacology Antitubercular Agents - therapeutic use Histone Deacetylase Inhibitors - pharmacology Histone Deacetylase Inhibitors - therapeutic use Histone Deacetylases Humans Mycobacterium tuberculosis PARASITOLOGY Rifampin - pharmacology TROPICAL MEDICINE Tuberculosis - drug therapy Tuberculosis - microbiology Tuberculosis, Multidrug-Resistant - drug therapy |
title | Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain |
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