A novel antimycobacterial compound acts as an intracellular iron chelator
Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M....
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Veröffentlicht in: | Antimicrobial agents and chemotherapy 2015-04, Vol.59 (4), p.2256-2264 |
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creator | Dragset, Marte S Poce, Giovanna Alfonso, Salvatore Padilla-Benavides, Teresita Ioerger, Thomas R Kaneko, Takushi Sacchettini, James C Biava, Mariangela Parish, Tanya Argüello, José M Steigedal, Magnus Rubin, Eric J |
description | Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound. |
doi_str_mv | 10.1128/aac.05114-14 |
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Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/aac.05114-14</identifier><identifier>PMID: 25645825</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Anti-Bacterial Agents ; Anti-Bacterial Agents - pharmacology ; Drug Resistance, Bacterial - drug effects ; Drug Resistance, Bacterial - genetics ; Ferrozine - metabolism ; Iron - metabolism ; Iron Chelating Agents ; Iron Chelating Agents - pharmacology ; Mechanisms of Action: Physiological Effects ; Microbial Sensitivity Tests ; Mycobacterium smegmatis ; Mycobacterium smegmatis - drug effects ; Mycobacterium smegmatis - genetics ; Mycobacterium tuberculosis ; Oxazoles - metabolism ; Pyrazoles ; Pyrazoles - chemical synthesis ; Pyrazoles - pharmacology ; Pyrimidinones ; Pyrimidinones - chemical synthesis ; Pyrimidinones - pharmacology ; RNA, Bacterial - metabolism ; Siderophores - metabolism</subject><ispartof>Antimicrobial agents and chemotherapy, 2015-04, Vol.59 (4), p.2256-2264</ispartof><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved. 2015 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a517t-34d8a7f31568ae354057dbd427cb06365a55dd10bafd602a80c2230f3c07ad123</citedby><cites>FETCH-LOGICAL-a517t-34d8a7f31568ae354057dbd427cb06365a55dd10bafd602a80c2230f3c07ad123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356758/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356758/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25645825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dragset, Marte S</creatorcontrib><creatorcontrib>Poce, Giovanna</creatorcontrib><creatorcontrib>Alfonso, Salvatore</creatorcontrib><creatorcontrib>Padilla-Benavides, Teresita</creatorcontrib><creatorcontrib>Ioerger, Thomas R</creatorcontrib><creatorcontrib>Kaneko, Takushi</creatorcontrib><creatorcontrib>Sacchettini, James C</creatorcontrib><creatorcontrib>Biava, Mariangela</creatorcontrib><creatorcontrib>Parish, Tanya</creatorcontrib><creatorcontrib>Argüello, José M</creatorcontrib><creatorcontrib>Steigedal, Magnus</creatorcontrib><creatorcontrib>Rubin, Eric J</creatorcontrib><title>A novel antimycobacterial compound acts as an intracellular iron chelator</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.</description><subject>Anti-Bacterial Agents</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Drug Resistance, Bacterial - drug effects</subject><subject>Drug Resistance, Bacterial - genetics</subject><subject>Ferrozine - metabolism</subject><subject>Iron - metabolism</subject><subject>Iron Chelating Agents</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Mechanisms of Action: Physiological Effects</subject><subject>Microbial Sensitivity Tests</subject><subject>Mycobacterium smegmatis</subject><subject>Mycobacterium smegmatis - drug effects</subject><subject>Mycobacterium smegmatis - genetics</subject><subject>Mycobacterium tuberculosis</subject><subject>Oxazoles - metabolism</subject><subject>Pyrazoles</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidinones</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - pharmacology</subject><subject>RNA, Bacterial - metabolism</subject><subject>Siderophores - metabolism</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1rGzEQxUVpqF23t5zDHlvoJvoaaX0JGNOmhkAu6VnMStpkw67kSLsG__ddx2lIDoWAQGj04_HePEJOGT1njFcXiPacAmOyZPIDmTO6rEoFS_WRzClVqpQVlTPyOecHOr1hST-RGQcloeIwJ5tVEeLOdwWGoe33NtZoB59a7Aob-20cgyumSS5wOqFow5DQ-q4bO0xFm2Io7L3vcIjpCzlpsMv-6_O9IH9-_bxd_y6vb64269V1icD0UArpKtSNYKAq9AIkBe1qJ7m2NVVCAQI4x2iNjVOUY0Ut54I2wlKNjnGxIJdH3e1Y995Zf7DUmW1qe0x7E7E1b39Ce2_u4s5IAUpDNQl8exZI8XH0eTB9mw-ZMPg4ZsOUVgIYaPYO9OBYCakn9McRtSnmnHzz4ohRcyjKrFZr81SUYXLCvx9xzD03D3FMYVra_9iz14lfhP-1KP4C8UybKQ</recordid><startdate>20150401</startdate><enddate>20150401</enddate><creator>Dragset, Marte S</creator><creator>Poce, Giovanna</creator><creator>Alfonso, Salvatore</creator><creator>Padilla-Benavides, Teresita</creator><creator>Ioerger, Thomas R</creator><creator>Kaneko, Takushi</creator><creator>Sacchettini, James C</creator><creator>Biava, Mariangela</creator><creator>Parish, Tanya</creator><creator>Argüello, José M</creator><creator>Steigedal, Magnus</creator><creator>Rubin, Eric J</creator><general>American Society for Microbiology</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>7QO</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20150401</creationdate><title>A novel antimycobacterial compound acts as an intracellular iron chelator</title><author>Dragset, Marte S ; Poce, Giovanna ; Alfonso, Salvatore ; Padilla-Benavides, Teresita ; Ioerger, Thomas R ; Kaneko, Takushi ; Sacchettini, James C ; Biava, Mariangela ; Parish, Tanya ; Argüello, José M ; Steigedal, Magnus ; Rubin, Eric J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a517t-34d8a7f31568ae354057dbd427cb06365a55dd10bafd602a80c2230f3c07ad123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Anti-Bacterial Agents</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Drug Resistance, Bacterial - drug effects</topic><topic>Drug Resistance, Bacterial - genetics</topic><topic>Ferrozine - metabolism</topic><topic>Iron - metabolism</topic><topic>Iron Chelating Agents</topic><topic>Iron Chelating Agents - pharmacology</topic><topic>Mechanisms of Action: Physiological Effects</topic><topic>Microbial Sensitivity Tests</topic><topic>Mycobacterium smegmatis</topic><topic>Mycobacterium smegmatis - drug effects</topic><topic>Mycobacterium smegmatis - genetics</topic><topic>Mycobacterium tuberculosis</topic><topic>Oxazoles - metabolism</topic><topic>Pyrazoles</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidinones</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - pharmacology</topic><topic>RNA, Bacterial - metabolism</topic><topic>Siderophores - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dragset, Marte S</creatorcontrib><creatorcontrib>Poce, Giovanna</creatorcontrib><creatorcontrib>Alfonso, Salvatore</creatorcontrib><creatorcontrib>Padilla-Benavides, Teresita</creatorcontrib><creatorcontrib>Ioerger, Thomas R</creatorcontrib><creatorcontrib>Kaneko, Takushi</creatorcontrib><creatorcontrib>Sacchettini, James C</creatorcontrib><creatorcontrib>Biava, Mariangela</creatorcontrib><creatorcontrib>Parish, Tanya</creatorcontrib><creatorcontrib>Argüello, José M</creatorcontrib><creatorcontrib>Steigedal, Magnus</creatorcontrib><creatorcontrib>Rubin, Eric J</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>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dragset, Marte S</au><au>Poce, Giovanna</au><au>Alfonso, Salvatore</au><au>Padilla-Benavides, Teresita</au><au>Ioerger, Thomas R</au><au>Kaneko, Takushi</au><au>Sacchettini, James C</au><au>Biava, Mariangela</au><au>Parish, Tanya</au><au>Argüello, José M</au><au>Steigedal, Magnus</au><au>Rubin, Eric J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel antimycobacterial compound acts as an intracellular iron chelator</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>59</volume><issue>4</issue><spage>2256</spage><epage>2264</epage><pages>2256-2264</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>25645825</pmid><doi>10.1128/aac.05114-14</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Anti-Bacterial Agents Anti-Bacterial Agents - pharmacology Drug Resistance, Bacterial - drug effects Drug Resistance, Bacterial - genetics Ferrozine - metabolism Iron - metabolism Iron Chelating Agents Iron Chelating Agents - pharmacology Mechanisms of Action: Physiological Effects Microbial Sensitivity Tests Mycobacterium smegmatis Mycobacterium smegmatis - drug effects Mycobacterium smegmatis - genetics Mycobacterium tuberculosis Oxazoles - metabolism Pyrazoles Pyrazoles - chemical synthesis Pyrazoles - pharmacology Pyrimidinones Pyrimidinones - chemical synthesis Pyrimidinones - pharmacology RNA, Bacterial - metabolism Siderophores - metabolism |
title | A novel antimycobacterial compound acts as an intracellular iron chelator |
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