Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo–Nitroreductase Complex

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of the American Chemical Society Vol. 145; no. 11; pp. 6453 - 6461
Main Authors:	Weng, Cheng, Yang, Hui, Loh, Boon Shing, Wong, Ming Wah, Ang, Wee Han
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 22-03-2023
Subjects:	Bacteria - metabolism Coordination Complexes - pharmacology Formates Methicillin-Resistant Staphylococcus aureus - metabolism Nitro Compounds - chemistry Nitroreductases - metabolism Prodrugs - pharmacology
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Abstract	Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru–arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox–active metal complexes for prodrug activation via bioinspired nitroreduction.
AbstractList	Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru–arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox–active metal complexes for prodrug activation via bioinspired nitroreduction. Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru-arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant . This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox-active metal complexes for prodrug activation via bioinspired nitroreduction.
Author	Loh, Boon Shing Ang, Wee Han Wong, Ming Wah Weng, Cheng Yang, Hui
AuthorAffiliation	Department of Chemistry NUS Graduate SchoolIntegrative Sciences and Engineering Programme
AuthorAffiliation_xml	– name: Department of Chemistry – name: NUS Graduate SchoolIntegrative Sciences and Engineering Programme
Author_xml	– sequence: 1 givenname: Cheng surname: Weng fullname: Weng, Cheng organization: Department of Chemistry – sequence: 2 givenname: Hui surname: Yang fullname: Yang, Hui organization: Department of Chemistry – sequence: 3 givenname: Boon Shing surname: Loh fullname: Loh, Boon Shing organization: Department of Chemistry – sequence: 4 givenname: Ming Wah orcidid: 0000-0003-2162-1220 surname: Wong fullname: Wong, Ming Wah email: chmwmw@nus.edu.sg organization: NUS Graduate SchoolIntegrative Sciences and Engineering Programme – sequence: 5 givenname: Wee Han orcidid: 0000-0003-2027-356X surname: Ang fullname: Ang, Wee Han email: ang.weehan@nus.edu.sg organization: NUS Graduate SchoolIntegrative Sciences and Engineering Programme
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/36881731$$D View this record in MEDLINE/PubMed
BookMark	eNptkLtOwzAUhi0EglLYmFFGBgK-Ns4IhQISt6HMkeucFFeJHWxHwMY78IY8CalaYGE68q_P_9H5dtGmdRYQOiD4hGBKThdKhxOmMaYs20ADIihOBaGjTTTAfZhmcsR20G4Ii_7JqSTbaIeNpCQZIwOkp8rPIRo7Tx5VfHZzsEYnE-cbFSG9gBZsCTYm50pH8EYlryY-Jyo5N87Y0BoPZXIHUdW1-_r4vDfRuz7qdFQBkrFr2hre9tBWpeoA--s5RE-Ty-n4Or19uLoZn92milEeU5YLLgXWhIkMeAVQAc1npaIZAKVU85xXOcO5zGdcUKJIBVyUlIg-KbkgbIiOVr2tdy8dhFg0Jmioa2XBdaGgmeSSjRjOevR4hWrvQvBQFa03jfLvBcHFUmux1Fqstfb44bq5mzVQ_sI_Hv9WL38tXOdtf-j_Xd8vDYOY
CitedBy_id	crossref_primary_10_1002_ange_202317901 crossref_primary_10_1002_anie_202310040 crossref_primary_10_1002_ange_202310040 crossref_primary_10_1002_hlca_202300100 crossref_primary_10_1002_anie_202317901 crossref_primary_10_1021_acs_jmedchem_3c01421 crossref_primary_10_1039_D3SC05326A crossref_primary_10_1016_j_jinorgbio_2024_112574
Cites_doi	10.1016/j.ejmech.2017.08.010 10.1021/om960840f 10.3390/molecules191117279 10.1002/ange.202000173 10.1038/nprot.2016.034 10.1021/acs.inorgchem.0c03505 10.1021/cr300177k 10.1038/35016103 10.1021/jacs.5b04097 10.1038/s41586-020-2741-7 10.1128/jb.182.11.3072-3080.2000 10.1038/s41592-021-01364-4 10.1002/anie.201909690 10.1021/acs.chemrev.5b00203 10.3389/fmicb.2015.00742 10.1021/jacs.8b07189 10.1021/ja061099y 10.1021/jacs.6b06229 10.1016/j.chempr.2020.06.002 10.1021/acs.jmedchem.8b00147 10.1021/es980923i 10.1021/acs.chemrev.9b00379 10.1021/om4009185 10.5937/savteh1701058t 10.1111/j.1574-6976.2008.00107.x 10.1021/acs.chemrev.6b00525 10.1038/nchem.1500 10.1039/d2sc05672k 10.1016/j.watres.2016.04.053 10.1039/c6sc00268d 10.1016/j.chembiol.2017.02.005 10.1038/nrclinonc.2012.171 10.1038/nchembio.2024 10.1073/pnas.1407927111 10.1039/d0cc04970k 10.1021/acs.jmedchem.7b00563 10.1021/jm5015742 10.1038/s42255-019-0151-7 10.1039/c2cc30730h 10.1021/acscentsci.1c00825 10.1038/nchem.2918 10.1021/ja2061038 10.1016/j.molmet.2019.05.012 10.1021/jacs.9b00594 10.1002/anie.201300747 10.1126/science.1171583 10.1021/jacsau.1c00262 10.1016/j.chembiol.2019.01.007 10.1038/s41586-019-1188-1 10.1039/c7sc00497d 10.1038/nbt1201-1168 10.1021/jm500455p 10.1002/ejoc.202200118 10.1128/jb.01161-10 10.1039/d0cb00150c
ContentType	Journal Article
Copyright	2023 American Chemical Society
Copyright_xml	– notice: 2023 American Chemical Society
DBID	CGR CUY CVF ECM EIF NPM AAYXX CITATION 7X8
DOI	10.1021/jacs.3c00237
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed CrossRef MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) CrossRef MEDLINE - Academic
DatabaseTitleList	MEDLINE
Database_xml	– sequence: 1 dbid: ECM name: MEDLINE url: https://search.ebscohost.com/login.aspx?direct=true&db=cmedm&site=ehost-live sourceTypes: Index Database
DeliveryMethod	fulltext_linktorsrc
Discipline	Chemistry
EISSN	1520-5126
EndPage	6461
ExternalDocumentID	10_1021_jacs_3c00237 36881731 d224694751
Genre	Research Support, Non-U.S. Gov't Journal Article
GroupedDBID	--- -DZ -ET -~X .DC .K2 4.4 55A 5GY 5RE 5VS 7~N 85S 8W4 AABXI ABFLS ABFRP ABMVS ABPPZ ABPTK ABQRX ABUCX ACGFO ACGFS ACJ ACNCT ACS ADHLV AEESW AENEX AFEFF AGXLV ALMA_UNASSIGNED_HOLDINGS AQSVZ BAANH BKOMP CS3 DU5 EBS ED~ F5P GGK GNL IH2 IH9 JG~ LG6 P2P ROL RXW TAE TAF TN5 UHB UI2 UKR UPT VF5 VG9 VQA W1F WH7 XSW YQT YZZ ZCA ~02 53G AAHBH ABJNI ACBEA AHGAQ CGR CUPRZ CUY CVF ECM EIF NPM AAYXX CITATION 7X8
ID	FETCH-LOGICAL-a324t-3954850c1357e4feefe29bda27ee222c494f930989b4521a1fe45d215989d4513
IEDL.DBID	ACS
ISSN	0002-7863
IngestDate	Fri Aug 16 05:39:59 EDT 2024 Fri Aug 23 00:58:26 EDT 2024 Sat Sep 28 08:19:09 EDT 2024 Sat Mar 25 02:48:50 EDT 2023
IsPeerReviewed	true
IsScholarly	true
Issue	11
Language	English
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-a324t-3954850c1357e4feefe29bda27ee222c494f930989b4521a1fe45d215989d4513
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ORCID	0000-0003-2162-1220 0000-0003-2027-356X
PMID	36881731
PQID	2784836307
PQPubID	23479
PageCount	9
ParticipantIDs	proquest_miscellaneous_2784836307 crossref_primary_10_1021_jacs_3c00237 pubmed_primary_36881731 acs_journals_10_1021_jacs_3c00237
PublicationCentury	2000
PublicationDate	20230322 2023-03-22
PublicationDateYYYYMMDD	2023-03-22
PublicationDate_xml	– month: 03 year: 2023 text: 20230322 day: 22
PublicationDecade	2020
PublicationPlace	United States
PublicationPlace_xml	– name: United States
PublicationTitle	Journal of the American Chemical Society
PublicationTitleAlternate	J. Am. Chem. Soc
PublicationYear	2023
Publisher	American Chemical Society
Publisher_xml	– name: American Chemical Society
References	ref9/cit9 ref45/cit45 ref3/cit3 ref27/cit27 ref56/cit56 ref16/cit16 ref52/cit52 ref23/cit23 ref8/cit8 ref31/cit31 ref2/cit2 ref34/cit34 ref37/cit37 ref20/cit20 ref48/cit48 ref17/cit17 ref10/cit10 ref35/cit35 ref53/cit53 ref19/cit19 ref21/cit21 ref42/cit42 ref46/cit46 ref49/cit49 ref13/cit13 ref24/cit24 ref38/cit38 ref50/cit50 ref54/cit54 ref6/cit6 ref36/cit36 ref18/cit18 ref11/cit11 ref25/cit25 ref29/cit29 Leonhartsberger S. (ref30/cit30) 2002; 4 ref32/cit32 ref39/cit39 ref14/cit14 ref5/cit5 ref51/cit51 ref43/cit43 ref28/cit28 ref40/cit40 ref26/cit26 ref55/cit55 ref12/cit12 ref15/cit15 ref41/cit41 ref22/cit22 ref33/cit33 ref4/cit4 ref47/cit47 ref1/cit1 ref44/cit44 ref7/cit7
References_xml	– ident: ref11/cit11 doi: 10.1016/j.ejmech.2017.08.010 – ident: ref43/cit43 doi: 10.1021/om960840f – ident: ref51/cit51 doi: 10.3390/molecules191117279 – ident: ref38/cit38 doi: 10.1002/ange.202000173 – ident: ref20/cit20 doi: 10.1038/nprot.2016.034 – ident: ref44/cit44 doi: 10.1021/acs.inorgchem.0c03505 – ident: ref17/cit17 doi: 10.1021/cr300177k – ident: ref19/cit19 doi: 10.1038/35016103 – ident: ref14/cit14 doi: 10.1021/jacs.5b04097 – ident: ref33/cit33 doi: 10.1038/s41586-020-2741-7 – ident: ref55/cit55 doi: 10.1128/jb.182.11.3072-3080.2000 – ident: ref25/cit25 doi: 10.1038/s41592-021-01364-4 – ident: ref22/cit22 doi: 10.1002/anie.201909690 – ident: ref26/cit26 doi: 10.1021/acs.chemrev.5b00203 – ident: ref34/cit34 doi: 10.3389/fmicb.2015.00742 – ident: ref8/cit8 doi: 10.1021/jacs.8b07189 – ident: ref23/cit23 doi: 10.1021/ja061099y – ident: ref5/cit5 doi: 10.1021/jacs.6b06229 – ident: ref7/cit7 doi: 10.1016/j.chempr.2020.06.002 – ident: ref4/cit4 doi: 10.1021/acs.jmedchem.8b00147 – ident: ref50/cit50 doi: 10.1021/es980923i – ident: ref1/cit1 doi: 10.1021/acs.chemrev.9b00379 – ident: ref52/cit52 doi: 10.1021/om4009185 – ident: ref54/cit54 doi: 10.5937/savteh1701058t – ident: ref3/cit3 doi: 10.1111/j.1574-6976.2008.00107.x – ident: ref13/cit13 doi: 10.1021/acs.chemrev.6b00525 – ident: ref48/cit48 doi: 10.1038/nchem.1500 – ident: ref28/cit28 doi: 10.1039/d2sc05672k – ident: ref49/cit49 doi: 10.1016/j.watres.2016.04.053 – ident: ref36/cit36 doi: 10.1039/c6sc00268d – ident: ref10/cit10 doi: 10.1016/j.chembiol.2017.02.005 – ident: ref6/cit6 doi: 10.1038/nrclinonc.2012.171 – ident: ref16/cit16 doi: 10.1038/nchembio.2024 – ident: ref31/cit31 doi: 10.1073/pnas.1407927111 – ident: ref46/cit46 doi: 10.1039/d0cc04970k – ident: ref12/cit12 doi: 10.1021/acs.jmedchem.7b00563 – ident: ref21/cit21 doi: 10.1021/jm5015742 – ident: ref32/cit32 doi: 10.1038/s42255-019-0151-7 – volume: 4 start-page: 269 year: 2002 ident: ref30/cit30 publication-title: J. Mol. Microbiol. Biotechnol. contributor: fullname: Leonhartsberger S. – ident: ref40/cit40 doi: 10.1039/c2cc30730h – ident: ref47/cit47 doi: 10.1021/acscentsci.1c00825 – ident: ref9/cit9 doi: 10.1038/nchem.2918 – ident: ref53/cit53 doi: 10.1021/ja2061038 – ident: ref56/cit56 doi: 10.1016/j.molmet.2019.05.012 – ident: ref45/cit45 doi: 10.1021/jacs.9b00594 – ident: ref42/cit42 doi: 10.1002/anie.201300747 – ident: ref18/cit18 doi: 10.1126/science.1171583 – ident: ref39/cit39 doi: 10.1021/jacsau.1c00262 – ident: ref2/cit2 doi: 10.1016/j.chembiol.2019.01.007 – ident: ref15/cit15 doi: 10.1038/s41586-019-1188-1 – ident: ref35/cit35 doi: 10.1039/c7sc00497d – ident: ref24/cit24 doi: 10.1038/nbt1201-1168 – ident: ref37/cit37 doi: 10.1021/jm500455p – ident: ref27/cit27 doi: 10.1002/ejoc.202200118 – ident: ref29/cit29 doi: 10.1128/jb.01161-10 – ident: ref41/cit41 doi: 10.1039/d0cb00150c
SSID	ssj0004281
Score	2.5084133
Snippet	Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique...
SourceID	proquest crossref pubmed acs
SourceType	Aggregation Database Index Database Publisher
StartPage	6453
SubjectTerms	Bacteria - metabolism Coordination Complexes - pharmacology Formates Methicillin-Resistant Staphylococcus aureus - metabolism Nitro Compounds - chemistry Nitroreductases - metabolism Prodrugs - pharmacology
Title	Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo–Nitroreductase Complex
URI	http://dx.doi.org/10.1021/jacs.3c00237 https://www.ncbi.nlm.nih.gov/pubmed/36881731 https://search.proquest.com/docview/2784836307
Volume	145
hasFullText	1
inHoldings	1
isFullTextHit
isPrint
link	http://sdu.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwjV3LSsQwFA0-Frrx_RhfRFB3lTZpm3Spo4MbRVDBXUmaGxiQVqYdcOk_-Id-ifd2OorCgNv0QchNc056bs5l7MREAFHo0kB463GD4sLAgoAAvFGInolVjhTdmwd196yvrskm52yGgi_IH6ioz2VB4KLm2aJQSBKIAvUffs4_Ch1Naa7SqewS3P8-TQBU1L8BaAarbNFlsPrffq2xlY4_8otJwNfZHJQbbKk_Ldu2yYrHNrcbEYnfI7urcIIMCz5oqSkEV13N24ZfTmyaDac_sdzwy2E1LEl2B8dvoSE9_vP9427YjKoR2bs2CHecVo8XeNtiT4Prx_5N0FVSCAwSpiaQZOuWhEUkEwWxB_AgMuuMUABIEIo4i30mw0xnNkY8N5GHOHHIBrDFxUkkt9lCWZWwy3hivbd4zafexbqwmTZJZlOtTWjIir7HjnFg8u5LqPNW5Ba4yaDWbrh67HQagvx1Yqox477jaXxyHEWSMkwJ1bjOSS7VMsUFqsd2JoH7fpPEzkRKRnv_6Mk-W6b68ZRUJsQBW2hGYzhk87UbH7VT7Auvccu9
link.rule.ids	315,782,786,2769,27085,27933,27934,56747,56797
linkProvider	American Chemical Society
linkToHtml	http://sdu.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwlV1NT9wwEB2V7QEuLeWjXaDFSOUYKYnz4RzLwmqrwgqJrcQtsuOxtBJKqk1W4sh_4B_yS5jJJiCQkOjVSayRx_F7ybPfAPzUAWLg28QLnXH0gWJ9z2CIHjqdEnrGJrWs6E6u0um1Oj1jmxyvPwtDQdTUU92K-M_uAmwTRI2yYIxJ1-BjnBAPZiY0uno-BhmqoGe7qUpkt8_99dOMQ0X9EofeIJctyIw__2d4m_CpY5Pi1yr9X-ADlluwPuqLuG1DMWt3ehM-iUviehVNl3khxi1RRe-0q4DbiJOVabMW_F9WaHEyr-Yli_BoxQU2rM4_3N1P582iWrDZa0PgJ3gtucHbHfg7PpuNJl5XV8HTRJ8aT7LJW-wXgYxTjByiwzAzVocpItGFIsoil0k_U5mJCN114DCKLXEDarFRHMhdGJRVid9AxMY5Q9dc4mykCpMpHWcmUUr7mo3ph3BEA5N370Wdt5J3SJ8c3NoN1xCO-0zk_1YWG2_cd9SnKadRZGFDl1gt65zFUyUTWq6G8HWVv6eeJAUTpDLYe0ckh7A-mV2c5-e_p3_2YYMry_N2szA8gEGzWOJ3WKvt8kc76x4BGCHUKg
linkToPdf	http://sdu.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1Na9wwEB2aFNpc0vQz2zatAu3RYFm2JR-T3SwJaZdAUujNSNYIFoId1l7IMf-h_7C_JDNeu6WFQOnVssWgr_fkJ70B-GQloox9HiXBBdqg-DhymGCEwWpCz8xpz4ru6aVefDezE7bJkeNdGAqipZraXsTnWX3jw-AwwFZBVKAqxhm9BY-zXBe83zqaXv6-CpkYOTJebXI1nHX_-2vGoqr9E4seIJg90Myf_UeIe7A7sEpxtBkGz-ER1i_g6XRM5vYSqqv-xDfhlLggztfQsFlWYt4TVoxmQybcThxvzJut4P-zworjZbOsWYxHL75ixyr9z7sfi2W3alZs-toRCApeU67x9hV8m59cTU-jIb9CZIlGdZFis7csrqTKNKYBMWBSOG8TjUi0oUqLNBQqLkzhUkJ5KwOmmSeOQE98mkn1GrbrpsZ9EJkLwVFZyINPTeUKY7PC5cbY2LJB_QQOqWHKYX60ZS99J7T14KdDc03g89gb5c3GauOB9w7HriqpFVngsDU267ZkEdWonJatCbzZ9OGvmhQFI7WSb_8hko_w5GI2L7-cLc7fwQ4nmOdTZ0nyHra71RoPYKv16w_9wLsHINHWrQ
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Targeting+Pathogenic+Formate-Dependent+Bacteria+with+a+Bioinspired+Metallo-Nitroreductase+Complex&rft.jtitle=Journal+of+the+American+Chemical+Society&rft.au=Weng%2C+Cheng&rft.au=Yang%2C+Hui&rft.au=Loh%2C+Boon+Shing&rft.au=Wong%2C+Ming+Wah&rft.date=2023-03-22&rft.eissn=1520-5126&rft.volume=145&rft.issue=11&rft.spage=6453&rft.epage=6461&rft_id=info:doi/10.1021%2Fjacs.3c00237&rft.externalDBID=NO_FULL_TEXT
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0002-7863&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0002-7863&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0002-7863&client=summon