7ZAX

Solution structure of thanatin-like derivative 7 in complex with K. pneumoniae LptA

Summary for 7ZAX

• Entry DOI: 10.2210/pdb7zax/pdb
• NMR Information: BMRB: 34716
• Descriptor: Lipopolysaccharide export system protein LptA, Thanatin-like derivative (2 entities in total)
• Functional Keywords: structure from cyana 3.98.13, antibiotic
• Biological source: Klebsiella pneumoniae; More
• Total number of polymer chains: 2
• Total formula weight: 16797.97

Authors

Oi, K.K.,Moehle, K.,Zerbe, O. (deposition date: 2022-03-22, release date: 2023-06-07, Last modification date: 2023-11-15)

Primary citation

Schuster, M.,Brabet, E.,Oi, K.K.,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.
Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae.
Sci Adv, 9:eadg3683-eadg3683, 2023

PubMed Abstract: 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 and strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge.

PubMed: 37224246
DOI: 10.1126/sciadv.adg3683

Experimental method

SOLUTION NMR