7zax
Solution structure of thanatin-like derivative 7 in complex with K. pneumoniae LptA
Structural highlights
FunctionA6TEL9_KLEP7 Involved in the assembly of lipopolysaccharide (LPS). Required for the translocation of LPS from the inner membrane to the outer membrane. May form a bridge between the inner membrane and the outer membrane, via interactions with LptC and LptD, thereby facilitating LPS transfer across the periplasm.[HAMAP-Rule:MF_01914] Publication Abstract from PubMedThe 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. References
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