Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC
Tuberculosis, caused by Mycobacterium tuberculosis , claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycli...
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| creator | Radhakrishnan, Anjana Brown, Chelsea M Guy, Collette S Cooper, Charlotte Pacheco-Gomez, Raul Stansfeld, Phillip J Fullam, Elizabeth |
| description | Tuberculosis, caused by
Mycobacterium tuberculosis
, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling
via
the LpqY-SugABC importer is essential for the virulence and survival of
Mtb
and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill
Mtb
with a novel mechanism of action
via
the mycobacterial trehalose LpqY-SugABC transport system.
Interrogation of the Pathogen Box identified diverse chemical scaffolds against the mycobacterial trehalose transporter. |
| doi_str_mv | 10.1039/d2md00104g |
| format | Article |
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Mycobacterium tuberculosis
, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling
via
the LpqY-SugABC importer is essential for the virulence and survival of
Mtb
and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill
Mtb
with a novel mechanism of action
via
the mycobacterial trehalose LpqY-SugABC transport system.
Interrogation of the Pathogen Box identified diverse chemical scaffolds against the mycobacterial trehalose transporter.</description><identifier>ISSN: 2632-8682</identifier><identifier>ISSN: 2040-2503</identifier><identifier>EISSN: 2632-8682</identifier><identifier>EISSN: 2040-2511</identifier><identifier>DOI: 10.1039/d2md00104g</identifier><identifier>PMID: 36320433</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Chemistry ; Chemotherapy ; Diagnostic agents ; Drug development ; Drug resistance ; Interrogation ; Malaria ; Pathogens ; Transportation systems ; Trehalose ; Tuberculosis ; Vector-borne diseases ; Virulence</subject><ispartof>MedChemComm, 2022-10, Vol.13 (1), p.1225-1233</ispartof><rights>This journal is © The Royal Society of Chemistry.</rights><rights>Copyright Royal Society of Chemistry 2022</rights><rights>This journal is © The Royal Society of Chemistry 2022 RSC</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c387t-bef467acce65b7c1555a42b68748135364ac5ab62d9f369c9967ee0415ac0c643</cites><orcidid>0000-0001-6245-1614 ; 0000-0001-8800-7669 ; 0000-0002-5153-0613 ; 0000-0003-2006-5015 ; 0000-0002-5785-546X ; 0000-0003-4855-4187</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579956/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9579956/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36320433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Radhakrishnan, Anjana</creatorcontrib><creatorcontrib>Brown, Chelsea M</creatorcontrib><creatorcontrib>Guy, Collette S</creatorcontrib><creatorcontrib>Cooper, Charlotte</creatorcontrib><creatorcontrib>Pacheco-Gomez, Raul</creatorcontrib><creatorcontrib>Stansfeld, Phillip J</creatorcontrib><creatorcontrib>Fullam, Elizabeth</creatorcontrib><title>Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC</title><title>MedChemComm</title><addtitle>RSC Med Chem</addtitle><description>Tuberculosis, caused by
Mycobacterium tuberculosis
, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling
via
the LpqY-SugABC importer is essential for the virulence and survival of
Mtb
and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill
Mtb
with a novel mechanism of action
via
the mycobacterial trehalose LpqY-SugABC transport system.
Interrogation of the Pathogen Box identified diverse chemical scaffolds against the mycobacterial trehalose transporter.</description><subject>Chemistry</subject><subject>Chemotherapy</subject><subject>Diagnostic agents</subject><subject>Drug development</subject><subject>Drug resistance</subject><subject>Interrogation</subject><subject>Malaria</subject><subject>Pathogens</subject><subject>Transportation systems</subject><subject>Trehalose</subject><subject>Tuberculosis</subject><subject>Vector-borne diseases</subject><subject>Virulence</subject><issn>2632-8682</issn><issn>2040-2503</issn><issn>2632-8682</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNpdks1r1UAUxYMottRu3CsDbkSIzncyG6F91Vp4oqAuXIWbyU1eymTmdSYpFvzjHfvqs7q6F87vHs5wpiieMvqaUWHedHzqKGVUDg-KQ64FL2td84f39oPiOKVLSilXjGllHhcHImtUCnFY_LzwM8YYBpjH4EnoybxB8hnmTRjQk9Pwg0S8RnCJpAmcI1NwaBeHxI0D-C4RGGD0ab69m25saMFmxxEcmSNuwIWEeQOftiFmgay3V9_LL8twcrp6UjzqszMe382j4tv7d19XH8r1p_OL1cm6tKKu5rLFXuoKrEWt2soypRRI3uq6kjUTSmgJVkGreWd6oY01RleIVDIFllotxVHxdue7XdoJO4s-B3LNNo4TxJsmwNj8q_hx0wzhujGqMkbpbPDyziCGqwXT3ExjsugceAxLanglmOSV4SKjL_5DL8MSfX5eprgyWnJjMvVqR9kYUorY78Mw2vzutTnjH89uez3P8PP78ffonxYz8GwHxGT36t-PIX4Bobapjw</recordid><startdate>20221019</startdate><enddate>20221019</enddate><creator>Radhakrishnan, Anjana</creator><creator>Brown, Chelsea M</creator><creator>Guy, Collette S</creator><creator>Cooper, Charlotte</creator><creator>Pacheco-Gomez, Raul</creator><creator>Stansfeld, Phillip J</creator><creator>Fullam, Elizabeth</creator><general>Royal Society of Chemistry</general><general>RSC</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T5</scope><scope>7T7</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6245-1614</orcidid><orcidid>https://orcid.org/0000-0001-8800-7669</orcidid><orcidid>https://orcid.org/0000-0002-5153-0613</orcidid><orcidid>https://orcid.org/0000-0003-2006-5015</orcidid><orcidid>https://orcid.org/0000-0002-5785-546X</orcidid><orcidid>https://orcid.org/0000-0003-4855-4187</orcidid></search><sort><creationdate>20221019</creationdate><title>Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC</title><author>Radhakrishnan, Anjana ; Brown, Chelsea M ; Guy, Collette S ; Cooper, Charlotte ; Pacheco-Gomez, Raul ; Stansfeld, Phillip J ; Fullam, Elizabeth</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-bef467acce65b7c1555a42b68748135364ac5ab62d9f369c9967ee0415ac0c643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Chemistry</topic><topic>Chemotherapy</topic><topic>Diagnostic agents</topic><topic>Drug development</topic><topic>Drug resistance</topic><topic>Interrogation</topic><topic>Malaria</topic><topic>Pathogens</topic><topic>Transportation systems</topic><topic>Trehalose</topic><topic>Tuberculosis</topic><topic>Vector-borne diseases</topic><topic>Virulence</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Radhakrishnan, Anjana</creatorcontrib><creatorcontrib>Brown, Chelsea M</creatorcontrib><creatorcontrib>Guy, Collette S</creatorcontrib><creatorcontrib>Cooper, Charlotte</creatorcontrib><creatorcontrib>Pacheco-Gomez, Raul</creatorcontrib><creatorcontrib>Stansfeld, Phillip J</creatorcontrib><creatorcontrib>Fullam, Elizabeth</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Radhakrishnan, Anjana</au><au>Brown, Chelsea M</au><au>Guy, Collette S</au><au>Cooper, Charlotte</au><au>Pacheco-Gomez, Raul</au><au>Stansfeld, Phillip J</au><au>Fullam, Elizabeth</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC</atitle><jtitle>MedChemComm</jtitle><addtitle>RSC Med Chem</addtitle><date>2022-10-19</date><risdate>2022</risdate><volume>13</volume><issue>1</issue><spage>1225</spage><epage>1233</epage><pages>1225-1233</pages><issn>2632-8682</issn><issn>2040-2503</issn><eissn>2632-8682</eissn><eissn>2040-2511</eissn><abstract>Tuberculosis, caused by
Mycobacterium tuberculosis
, claims ∼1.5 million lives annually. Effective chemotherapy is essential to control TB, however the emergence of drug-resistant strains of TB have seriously threatened global attempts to control and eradicate this deadly pathogen. Trehalose recycling
via
the LpqY-SugABC importer is essential for the virulence and survival of
Mtb
and inhibiting or hijacking this transport system is an attractive approach for the development of novel anti-tubercular and diagnostic agents. Therefore, we interrogated the drug-like compounds in the open-source Medicines for Malaria Pathogen Box and successfully identified seven compounds from the TB, kinetoplastids and reference compound disease sets that recognise LpqY. The molecules have diverse chemical scaffolds, are not specific trehalose analogues, and may be used as novel templates to facilitate the development of therapeutics that kill
Mtb
with a novel mechanism of action
via
the mycobacterial trehalose LpqY-SugABC transport system.
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| source | Royal Society Of Chemistry Journals 2008-; PubMed Central |
| subjects | Chemistry Chemotherapy Diagnostic agents Drug development Drug resistance Interrogation Malaria Pathogens Transportation systems Trehalose Tuberculosis Vector-borne diseases Virulence |
| title | Interrogation of the Pathogen Box reveals small molecule ligands against the mycobacterial trehalose transporter LpqY-SugABC |
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