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Publication Abstract from PubMed

The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.

Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae.,Schuster M, Brabet E, Oi KK, Desjonqueres N, Moehle K, Le Poupon K, Hell S, Gable S, Rithie V, Dillinger S, Zbinden P, Luther A, Li C, Stiegeler S, D'Arco C, Locher H, Remus T, DiMaio S, Motta P, Wach A, Jung F, Upert G, Obrecht D, Benghezal M, Zerbe O Sci Adv. 2023 May 24;9(21):eadg3683. doi: 10.1126/sciadv.adg3683. Epub 2023 May , 24. PMID:37224246^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.