{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T02:33:57Z","timestamp":1776911637876,"version":"3.51.2"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"SSGCID"},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH"},{"DOI":"10.13039\/100004415","name":"NATO","doi-asserted-by":"crossref","award":["984835"],"award-info":[{"award-number":["984835"]}],"id":[{"id":"10.13039\/100004415","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis\/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac065","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:12:31Z","timestamp":1645618351000},"page":"1625-1634","source":"Crossref","is-referenced-by-count":10,"title":["Broad-spectrum <i>in vitro<\/i> activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and <i>Leishmania major<\/i>"],"prefix":"10.1093","volume":"77","author":[{"given":"Jua","family":"Iwasaki","sequence":"first","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"},{"name":"Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia , Nedlands, Western Australia, 6008, Australia"},{"name":"Centre for Child Health Research, University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald D.","family":"Lorimer","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirella","family":"Vivoli-Vega","sequence":"additional","affiliation":[{"name":"Department of Biosciences , Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD, UK"},{"name":"Living Systems Institute , Stocker Road, Exeter, EX4 4QD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily A.","family":"Kibble","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"},{"name":"School of Veterinary and Life Sciences, Murdoch University , Perth, WA, Australia"},{"name":"DMTC Limited, Level 2 , 24 Wakefield St, Hawthorn, VIC 3122, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher S.","family":"Peacock","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Abendroth","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen J.","family":"Mayclin","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Dranow","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phillip G.","family":"Pierce","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"David","family":"Fox","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"},{"name":"Beryllium, Inc. , 7869 NE Day Road West, Bainbridge Island, WA 98110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Lewis","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole M.","family":"Bzdyl","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofie S.","family":"Kristensen","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J. J.","family":"Inglis","sequence":"additional","affiliation":[{"name":"Department of Microbiology, PathWest Laboratory Medicine , Nedlands, WA 6009, Australia"},{"name":"Medical School, University of Western Australia , Nedlands, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlene M.","family":"Kahler","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9584-6783","authenticated-orcid":false,"given":"Charles S.","family":"Bond","sequence":"additional","affiliation":[{"name":"School of Molecular Sciences, The University of Western Australia , Perth, Western Australia, 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Hasenkopf","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg , Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Seufert","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg , Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg , Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down , Salisbury, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew E.","family":"Scott","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down , Salisbury, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isobel H.","family":"Norville","sequence":"additional","affiliation":[{"name":"Defence Science and Technology Laboratory, Porton Down , Salisbury, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Myler","sequence":"additional","affiliation":[{"name":"Seattle Structural Genomics Center for Infectious Disease , 307 Westlake Avenue North, Seattle, WA, 98109, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Holzgrabe","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg , Am Hubland, 97074 W\u00fcrzburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4073-0505","authenticated-orcid":false,"given":"Nicholas J.","family":"Harmer","sequence":"additional","affiliation":[{"name":"Department of Biosciences , Geoffrey Pope Building, Stocker Road, Exeter, EX4 4QD, UK"},{"name":"Living Systems Institute , Stocker Road, Exeter, EX4 4QD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitali","family":"Sarkar-Tyson","sequence":"additional","affiliation":[{"name":"Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, The University of Western Australia , Perth, Western Australia, 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"2022053122484116400_dkac065-B1","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.3389\/fphar.2018.01425","article-title":"FKBP ligands\u2014where we are and where to go?","volume":"9","author":"Kolos","year":"2018","journal-title":"Front Pharmacol"},{"key":"2022053122484116400_dkac065-B2","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nrmicro3232","article-title":"Targeting virulence: can we make evolution-proof drugs?","volume":"12","author":"Allen","year":"2014","journal-title":"Nat Rev Microbiol"},{"key":"2022053122484116400_dkac065-B3","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1128\/iai.57.4.1255-1262.1989","article-title":"A Legionella pneumophila gene encoding a species-specific surface protein potentiates initiation of intracellular infection","volume":"57","author":"Cianciotto","year":"1989","journal-title":"Infect Immun"},{"key":"2022053122484116400_dkac065-B4","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.1128\/IAI.00134-11","article-title":"A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence","volume":"79","author":"Norville","year":"2011","journal-title":"Infect Immun"},{"key":"2022053122484116400_dkac065-B5","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1111\/j.1365-2958.1993.tb01168.x","article-title":"Chlamydia trachomatis Mip-like protein has peptidylprolyl cis\/trans isomerase activity that is inhibited by FK506 and rapamycin and is implicated in initiation of chlamydial infection","volume":"7","author":"Lundemose","year":"1993","journal-title":"Mol Microbiol"},{"key":"2022053122484116400_dkac065-B6","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1111\/j.1365-2958.2005.04859.x","article-title":"Ng-MIP, a surface-exposed lipoprotein of Neisseria gonorrhoeae, has a peptidyl-prolyl cis\/trans isomerase (PPIase) activity and is involved in persistence in macrophages","volume":"58","author":"Leuzzi","year":"2005","journal-title":"Mol Microbiol"},{"key":"2022053122484116400_dkac065-B7","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ijantimicag.2016.06.020","article-title":"Inhibitors of macrophage infectivity potentiator-like PPIases affect neisserial and chlamydial pathogenicity","volume":"48","author":"Reimer","year":"2016","journal-title":"Int J Antimicrob Agents"},{"key":"2022053122484116400_dkac065-B8","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1002\/j.1460-2075.1995.tb07245.x","article-title":"Secretion by Trypanosoma cruzi of a peptidyl-prolyl cis-trans isomerase involved in cell infection","volume":"14","author":"Moro","year":"1995","journal-title":"EMBO J"},{"key":"2022053122484116400_dkac065-B9","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nsb0901-779","article-title":"Crystal structure of Mip, a prolylisomerase from Legionella pneumophila","volume":"8","author":"Riboldi-Tunnicliffe","year":"2001","journal-title":"Nat Struct Mol Biol"},{"key":"2022053122484116400_dkac065-B10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-5793(01)02326-2","article-title":"Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis\/trans isomerases","volume":"495","author":"Schiene-Fischer","year":"2001","journal-title":"FEBS Lett"},{"key":"2022053122484116400_dkac065-B11","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1365-2958.1993.tb00917.x","article-title":"Immunophilins: structure-function relationship and possible role in microbial pathogenicity","volume":"10","author":"Hacker","year":"1993","journal-title":"Mol Microbiol"},{"key":"2022053122484116400_dkac065-B12","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0092-8674(91)90124-H","article-title":"Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes","volume":"66","author":"Liu","year":"1991","journal-title":"Cell"},{"key":"2022053122484116400_dkac065-B13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12154-008-0003-5","article-title":"Rapamycin and mTOR kinase inhibitors","volume":"1","author":"Ballou","year":"2008","journal-title":"J Chem Biol"},{"key":"2022053122484116400_dkac065-B14","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1472-6807-8-17","article-title":"Solution structure of the Legionella pneumophila Mip-rapamycin complex","volume":"8","author":"Ceymann","year":"2008","journal-title":"BMC Struct Biol"},{"key":"2022053122484116400_dkac065-B15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1021\/jm101156y","article-title":"Pipecolic acid derivatives as small-molecule inhibitors of the Legionella MIP protein","volume":"54","author":"Juli","year":"2011","journal-title":"J Med Chem"},{"key":"2022053122484116400_dkac065-B16","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1016\/j.bbagen.2014.12.018","article-title":"FKBPs in bacterial infections","volume":"1850","author":"Unal","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"2022053122484116400_dkac065-B17","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1042\/BJ20110345","article-title":"The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development","volume":"437","author":"Norville","year":"2011","journal-title":"Biochem J"},{"key":"2022053122484116400_dkac065-B18","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1128\/AAC.01875-13","article-title":"A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins","volume":"58","author":"Begley","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"2022053122484116400_dkac065-B19","doi-asserted-by":"crossref","first-page":"493","DOI":"10.2174\/187152609789105687","article-title":"The Seattle Structural Genomics Center for Infectious Disease (SSGCID)","volume":"9","author":"Myler","year":"2009","journal-title":"Infect Disord Drug Targets"},{"key":"2022053122484116400_dkac065-B20","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ab.2017.08.004","article-title":"A miniaturized peptidyl-prolyl isomerase enzyme assay","volume":"536","author":"Vivoli","year":"2017","journal-title":"Anal Biochem"},{"key":"2022053122484116400_dkac065-B21","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View - molecular graphics for all devices - from smartphones to workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinformatics"},{"key":"2022053122484116400_dkac065-B22","first-page":"1","volume-title":"Leishmania: Methods and Protocols","author":"Zilberstein","year":"2019"},{"key":"2022053122484116400_dkac065-B23","doi-asserted-by":"crossref","first-page":"13355","DOI":"10.1021\/acs.jmedchem.0c00911","article-title":"Targeting protein folding: a novel approach for the treatment of pathogenic bacteria","volume":"63","author":"Scheuplein","year":"2020","journal-title":"J Med Chem"},{"key":"2022053122484116400_dkac065-B24","doi-asserted-by":"crossref","first-page":"5134","DOI":"10.1016\/j.bmc.2016.08.025","article-title":"Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei","volume":"24","author":"Seufert","year":"2016","journal-title":"Bioorg Med Chem"},{"key":"2022053122484116400_dkac065-B25","doi-asserted-by":"crossref","first-page":"W441","DOI":"10.1093\/nar\/gkp253","article-title":"IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding","volume":"37","author":"Cer","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"2022053122484116400_dkac065-B26","doi-asserted-by":"crossref","first-page":"e1002027","DOI":"10.1371\/journal.ppat.1002027","article-title":"Transcriptome analysis of Neisseria meningitidis in human whole blood and mutagenesis studies identify virulence factors involved in blood survival","volume":"7","author":"Echenique-Rivera","year":"2011","journal-title":"PLoS Pathog"},{"key":"2022053122484116400_dkac065-B27","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1080\/14787210.2018.1522249","article-title":"Multidrug-resistant Klebsiella pneumoniae: challenges for treatment, prevention and infection control","volume":"16","author":"Bassetti","year":"2018","journal-title":"Expert Rev Anti Infect Ther"},{"key":"2022053122484116400_dkac065-B28","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrd4572","article-title":"ESKAPEing the labyrinth of antibacterial discovery","volume":"14","author":"Tommasi","year":"2015","journal-title":"Nat Rev Drug Discov"},{"key":"2022053122484116400_dkac065-B29","doi-asserted-by":"crossref","first-page":"e1004399","DOI":"10.1371\/journal.ppat.1004399","article-title":"Unveiling the intracellular survival gene kit of trypanosomatid parasites","volume":"10","author":"Bartholomeu","year":"2014","journal-title":"PLoS Pathog"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/6\/1625\/43893516\/dkac065.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/77\/6\/1625\/43893516\/dkac065.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T22:52:16Z","timestamp":1654037536000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/77\/6\/1625\/6542617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3,4]]},"published-print":{"date-parts":[[2022,5,29]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkac065","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,6,1]]},"published":{"date-parts":[[2022,3,4]]}}}