{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:16:20Z","timestamp":1789470980595,"version":"build-2803163510"},"reference-count":19,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,1,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Carbapenem-resistant\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    (CREs) are described by the Centers for Disease Control as an urgent threat, and there is a critical need for new therapeutic agents able to treat infections caused by these pathogens. Herein, we describe the microbiological profile, the mechanism f action, and the\n                    <jats:italic>in vitro<\/jats:italic>\n                    safety as well as the pharmacokinetic (PK)\/PD profile of SMT-738, a small molecule belonging to a new chemical class. SMT-738 is active against Enterobacterales [including multi-drug-resistant\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    with 90% of isolates having a minimum inhibitory concentration (MIC\n                    <jats:sub>90<\/jats:sub>\n                    ) of 1 \u00b5g\/mL and\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    2 \u00b5g\/mL] and inactive against a broad panel of Gram-negative and Gram-positive pathogens. SMT-738 displays rapid bactericidal activity (2\u20134 h) and has a low propensity for resistance development (less than ~10\n                    <jats:sup>\u22129<\/jats:sup>\n                    ). Characterization of resistant mutants following exposure to SMT-738 identified mutations within the lipoprotein transport complex (LolCDE), a clinically unexploited and essential bacterial molecular target in Gram-negative bacteria. SMT-738 has a promising\n                    <jats:italic>in vitro<\/jats:italic>\n                    toxicology profile. Furthermore, PK studies demonstrated that when dosed intravenously, SMT-738 maintained exposure levels across infection sites (bloodstream\/urinary tract\/lung). Proof-of-concept studies across multiple murine\n                    <jats:italic>in vivo<\/jats:italic>\n                    infection models (bloodstream\/pneumonia\/urinary tract) demonstrated that SMT-738 significantly reduced the bacterial burden compared to baseline and vehicle control. SMT-738 represents a promising novel drug candidate being developed to address clinically challenging serious life-threatening infections caused by highly resistant\n                    <jats:italic>Enterobacteriaceae<\/jats:italic>\n                    including CRE.\n                  <\/jats:p>","DOI":"10.1128\/aac.00695-23","type":"journal-article","created":{"date-parts":[[2023,12,12]],"date-time":"2023-12-12T09:01:25Z","timestamp":1702371685000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3734-9222","authenticated-orcid":false,"given":"E. B. M.","family":"Breidenstein","sequence":"first","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Khan","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Coward","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Avis","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Abdulle","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-7821","authenticated-orcid":false,"given":"C.-M.","family":"Li","sequence":"additional","affiliation":[{"name":"Summit Therapeutics , Menlo Park, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3179-6622","authenticated-orcid":false,"given":"C. S.","family":"Mason","sequence":"additional","affiliation":[{"name":"Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00079-17"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00397-20"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medine.2022.09.002"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-015-1865-4"},{"key":"e_1_3_3_7_2","unstructured":"Pew Trust . 2018. Antibiotics currently in global clinical development. Available from: https:\/\/www.pewtrusts.org\/en\/research-and-analysis\/data-visualizations\/2014\/antibiotics-currently-in-clinical-development"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24965-1"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00051-15"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.179.9.2857-2862.1997"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02151-17"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1806822115"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00618-19"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/495141a"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S173867"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/35008635"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00203-004-0682-4"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1271\/bbb.90451"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.02352-14"},{"key":"e_1_3_3_21_2","first-page":"1898","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically","author":"CLSI","year":"2018","unstructured":"CLSI . 2018. CLSI standard M07, p 1898. In Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 11th ed. CLSI, Wayne, PA, USA.","edition":"11"},{"key":"e_1_3_3_22_2","first-page":"1898","volume-title":"Performance standards for antimicrobial susceptibility testing","author":"CLSI","year":"2019","unstructured":"CLSI . 2019. CLSI supplement M100, p 1898. In Performance standards for antimicrobial susceptibility testing, 31st ed. CLSI, Wayne, PA, USA.","edition":"31"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00695-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00695-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T09:03:18Z","timestamp":1704877398000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00695-23"}},"subtitle":[],"editor":[{"given":"Jared A.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,10]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,10]]}},"alternative-id":["10.1128\/aac.00695-23"],"URL":"https:\/\/doi.org\/10.1128\/aac.00695-23","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,10]]},"assertion":[{"value":"2023-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00695-23"}}