Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem
The objective of this study was to find molecules with anti-mycobacterial activity from a natural compounds library, investigate their mechanisms of resistance, and assess their synergy with antibiotics. We screened a library of 2582 natural compounds with Mycobacterium aurum with the aim of identif...
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| Veröffentlicht in: | Tuberculosis (Edinburgh, Scotland) Scotland), 2017-12, Vol.107, p.111-118 |
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| container_title | Tuberculosis (Edinburgh, Scotland) |
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| creator | Huang, Wei Briffotaux, Julien Wang, Xinwei Liu, Lili Hao, Pei Cimino, Mena Buchieri, Maria Virginia Namouchi, Amine Ainsa, Jose-Antonio Gicquel, Brigitte |
| description | The objective of this study was to find molecules with anti-mycobacterial activity from a natural compounds library, investigate their mechanisms of resistance, and assess their synergy with antibiotics. We screened a library of 2582 natural compounds with Mycobacterium aurum with the aim of identifying molecules with anti-mycobacterial activity. The hits with the lowest MICs in M. aurum were also tested for their antimicrobial activity in other mycobacterial species including M. tuberculosis complex strains. The chequerboard titration assay was chosen for determining drug interactions in vitro. Spontaneous resistant mutants were isolated and their whole genome sequences compared to wild type and resistant mutants to identify resistance mechanisms. We found that ionophores show anti-mycobacterial activity in vitro. Resistance mechanism to ionophores is mediated by the MmpL5-MmpS5 transporter overexpression. Ionophore A23187 enhanced beta-lactam activity in M. tuberculosis infected macrophage. It will help in the investigation of new drug combinations against bacterial infections including tuberculosis. |
| doi_str_mv | 10.1016/j.tube.2017.09.001 |
| format | Article |
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We screened a library of 2582 natural compounds with Mycobacterium aurum with the aim of identifying molecules with anti-mycobacterial activity. The hits with the lowest MICs in M. aurum were also tested for their antimicrobial activity in other mycobacterial species including M. tuberculosis complex strains. The chequerboard titration assay was chosen for determining drug interactions in vitro. Spontaneous resistant mutants were isolated and their whole genome sequences compared to wild type and resistant mutants to identify resistance mechanisms. We found that ionophores show anti-mycobacterial activity in vitro. Resistance mechanism to ionophores is mediated by the MmpL5-MmpS5 transporter overexpression. Ionophore A23187 enhanced beta-lactam activity in M. tuberculosis infected macrophage. It will help in the investigation of new drug combinations against bacterial infections including tuberculosis.</description><identifier>ISSN: 1472-9792</identifier><identifier>EISSN: 1873-281X</identifier><identifier>DOI: 10.1016/j.tube.2017.09.001</identifier><identifier>PMID: 29050757</identifier><language>eng</language><publisher>Scotland: Elsevier Ltd</publisher><subject>Antibiotics, Antitubercular - pharmacology ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Calcimycin - pharmacology ; Calcium Ionophores - pharmacology ; Carbapenems - pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Resistance, Bacterial - genetics ; Drug Synergism ; Genotype ; Humans ; Macrophages - microbiology ; Membrane Transport Proteins - genetics ; Membrane Transport Proteins - metabolism ; Microbial Sensitivity Tests ; Mutation ; Mycobacterium tuberculosis - drug effects ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - growth & development</subject><ispartof>Tuberculosis (Edinburgh, Scotland), 2017-12, Vol.107, p.111-118</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-3e8953a5e27d3766323b070a9115c544072ad4bf7468b47e3087de68f573f9563</citedby><cites>FETCH-LOGICAL-c356t-3e8953a5e27d3766323b070a9115c544072ad4bf7468b47e3087de68f573f9563</cites><orcidid>0000-0002-1498-7059 ; 0000-0002-8569-5184</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1472979217301968$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29050757$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Wei</creatorcontrib><creatorcontrib>Briffotaux, Julien</creatorcontrib><creatorcontrib>Wang, Xinwei</creatorcontrib><creatorcontrib>Liu, Lili</creatorcontrib><creatorcontrib>Hao, Pei</creatorcontrib><creatorcontrib>Cimino, Mena</creatorcontrib><creatorcontrib>Buchieri, Maria Virginia</creatorcontrib><creatorcontrib>Namouchi, Amine</creatorcontrib><creatorcontrib>Ainsa, Jose-Antonio</creatorcontrib><creatorcontrib>Gicquel, Brigitte</creatorcontrib><title>Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem</title><title>Tuberculosis (Edinburgh, Scotland)</title><addtitle>Tuberculosis (Edinb)</addtitle><description>The objective of this study was to find molecules with anti-mycobacterial activity from a natural compounds library, investigate their mechanisms of resistance, and assess their synergy with antibiotics. 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We screened a library of 2582 natural compounds with Mycobacterium aurum with the aim of identifying molecules with anti-mycobacterial activity. The hits with the lowest MICs in M. aurum were also tested for their antimicrobial activity in other mycobacterial species including M. tuberculosis complex strains. The chequerboard titration assay was chosen for determining drug interactions in vitro. Spontaneous resistant mutants were isolated and their whole genome sequences compared to wild type and resistant mutants to identify resistance mechanisms. We found that ionophores show anti-mycobacterial activity in vitro. Resistance mechanism to ionophores is mediated by the MmpL5-MmpS5 transporter overexpression. Ionophore A23187 enhanced beta-lactam activity in M. tuberculosis infected macrophage. 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| ispartof | Tuberculosis (Edinburgh, Scotland), 2017-12, Vol.107, p.111-118 |
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| subjects | Antibiotics, Antitubercular - pharmacology Bacterial Proteins - genetics Bacterial Proteins - metabolism Calcimycin - pharmacology Calcium Ionophores - pharmacology Carbapenems - pharmacology Cells, Cultured Dose-Response Relationship, Drug Drug Resistance, Bacterial - genetics Drug Synergism Genotype Humans Macrophages - microbiology Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Microbial Sensitivity Tests Mutation Mycobacterium tuberculosis - drug effects Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - growth & development |
| title | Ionophore A23187 shows anti-tuberculosis activity and synergy with tebipenem |
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