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To date, antibiotics targeting bacterial central metabolism have been poorly investigated. By determining the minimal inhibitory concentration (MIC) of desmethylphosphinothricin (Glu-\u03b3-PH), an analogue of glutamate with a phosphinic moiety replacing the \u03b3-carboxyl group, we previously showed its promising antibacterial activity on Escherichia coli. Herein, we synthetized and determined the growth inhibition exerted on E. coli by an L-Leu dipeptide derivative of Glu-\u03b3-PH (L-Leu-D,L-Glu-\u03b3-PH). Furthermore, we compared the growth inhibition obtained with this dipeptide with that exerted by the free amino acid, i.e., Glu-\u03b3-PH, and by their phosphonic and non-desmethylated analogues. All the tested compounds were more effective when assayed in a chemically-defined minimal medium. The dipeptide L-Leu-D,L-Glu-\u03b3-PH had a significantly improved antibacterial activity (2 \u03bcg\/mL), at a concentration between the non-desmethytaled (0.1 \u03bcg\/mL) and the phosphonic (80 \u03bcg\/mL) analogues. Also, in Bacillus subtilis, the dipeptide L-Leu-D,L-Glu-\u03b3-PH displayed an activity comparable to that of the antibiotic amoxicillin. This work highlights the antibacterial relevance of the phosphinic pharmacophore and proposes new avenues for the development of novel antimicrobial drugs containing the phosphinic moiety.<\/jats:p>","DOI":"10.3390\/biom13101451","type":"journal-article","created":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T03:04:18Z","timestamp":1695783858000},"page":"1451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Desmethylphosphinothricin Dipeptide Derivative Effectively Inhibits Escherichia coli and Bacillus subtilis Growth"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2833-9834","authenticated-orcid":false,"given":"Maxim A.","family":"Khomutov","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0324-1398","authenticated-orcid":false,"given":"Fabio","family":"Giovannercole","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, I-04100 Latina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Onillon","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, I-04100 Latina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija V.","family":"Demiankova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, Bol\u2019shaya Pirogovskaya 11, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byazilya F.","family":"Vasilieva","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, Bol\u2019shaya Pirogovskaya 11, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur I.","family":"Salikhov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey N.","family":"Kochetkov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-1031","authenticated-orcid":false,"given":"Olga V.","family":"Efremenkova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, Bol\u2019shaya Pirogovskaya 11, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6833-7855","authenticated-orcid":false,"given":"Alex R.","family":"Khomutov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3536-9927","authenticated-orcid":false,"given":"Daniela","family":"De Biase","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, I-04100 Latina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12175","DOI":"10.1073\/pnas.1500873112","article-title":"Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes","volume":"112","author":"Ju","year":"2015","journal-title":"Proc. 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