Hermant, YannPalpal-Latoc, DenniseKovalenko, NadiiaCameron, Alan JBrimble, Margaret AHarris, Paul WR2023-03-092023-03-092021-08(2021). Journal of Natural Products, 84(8), 2165-2174.0163-3864https://hdl.handle.net/2292/63250Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from <i>Brevibacillus laterosporus</i> through a global genome-mining approach. Both laterocidine and brevicidine exhibit potent antimicrobial activity toward Gram-negative bacteria, including difficult-to-treat <i>Pseudonomas aeruginosa</i> and colistin-resistant <i>Escherichia coli</i>, and a low risk of resistance development. Herein, we report the first total syntheses of laterocidine and brevicidine via an efficient and high-yielding combination of solid-phase synthesis and solution-phase macrolactamization. The crucial depsipeptide bond of the macrolactone rings of laterocidine and brevicidine was established on-resin between the side-chain hydroxy group of Thr⁹ with Alloc-Gly-OH or Alloc-Ser(<i>t</i>Bu)-OH, respectively. A conserved glycine residue within the lactone macrocycle is exploited for the initial immobilization onto the hyper acid-labile 2-chlorotrityl chloride resin, subsequently enabling an efficient solution-phase macrocyclization to yield laterocidine and brevicidine in 36% and 10% overall yields, respectively (with respect to resin loading). A biological evaluation against both Gram-positive and Gram-negative bacteria demonstrated that synthetic laterocidine and brevicidine possessed a potent and selective antimicrobial activity toward Gram-negative bacteria, in accordance with the isolated compounds.Print-ElectronicItems in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmGram-Negative BacteriaGram-Positive BacteriaAntimicrobial Cationic PeptidesAnti-Bacterial AgentsMicrobial Sensitivity TestsMolecular StructureBrevibacillusInfectious DiseasesVaccine RelatedAntimicrobial ResistanceEmerging Infectious DiseasesBiodefensePreventionBiotechnology5 Development of treatments and therapeutic interventions5.1 PharmaceuticalsInfectionScience & TechnologyLife Sciences & BiomedicinePlant SciencesChemistry, MedicinalPharmacology & PharmacyRESISTANCECYCLIZATIONDAPTOMYCINPATHOGENS03 Chemical Sciences06 Biological Sciences11 Medical and Health SciencesJournal Article10.1021/acs.jnatprod.1c002222023-02-28Copyright: The authors34338512 (pubmed)http://purl.org/eprint/accessRights/RetrictedAccess1520-6025