{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:07:37Z","timestamp":1792181257866,"version":"4.4.0"},"reference-count":195,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T00:00:00Z","timestamp":1670976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["270650915"],"award-info":[{"award-number":["270650915"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["91705741"],"award-info":[{"award-number":["91705741"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Egyptian Ministry of Higher Education and Scientific Research","award":["270650915"],"award-info":[{"award-number":["270650915"]}]},{"name":"The Egyptian Ministry of Higher Education and Scientific Research","award":["91705741"],"award-info":[{"award-number":["91705741"]}]},{"name":"German Academic Exchange Service","award":["270650915"],"award-info":[{"award-number":["270650915"]}]},{"name":"German Academic Exchange Service","award":["91705741"],"award-info":[{"award-number":["91705741"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure\u2013activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed.<\/jats:p>","DOI":"10.3390\/ph15121553","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T01:52:34Z","timestamp":1670982754000},"page":"1553","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9185-5156","authenticated-orcid":false,"given":"Talea","family":"Knak","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-9538","authenticated-orcid":false,"given":"Mona A.","family":"Abdullaziz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-6974","authenticated-orcid":false,"given":"Stefan","family":"H\u00f6fmann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro A.","family":"Alves Avelar","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Klein","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0835-6960","authenticated-orcid":false,"given":"Matthew","family":"Martin","sequence":"additional","affiliation":[{"name":"Initiative for Science & Society, Duke University, 140 Science Drive, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazie, Universit\u00e4t Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-4698","authenticated-orcid":false,"given":"Nobutada","family":"Tanaka","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9474-4224","authenticated-orcid":false,"given":"Thomas","family":"Kurz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazeutische und Medizinische Chemie, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstra\u00dfe 1, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1042\/bj2950517","article-title":"Isoprenoid Biosynthesis in Bacteria: A Novel Pathway for the Early Steps Leading to Isopentenyl Diphosphate","volume":"295","author":"Rohmer","year":"1993","journal-title":"Biochem. 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