| Structural highlights
Function
LPTA_ECOLI 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][1] [2] [3] [4] [5]
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sperandeo P, Pozzi C, Deho G, Polissi A. Non-essential KDO biosynthesis and new essential cell envelope biogenesis genes in the Escherichia coli yrbG-yhbG locus. Res Microbiol. 2006 Jul-Aug;157(6):547-58. Epub 2006 Feb 9. PMID:16765569 doi:10.1016/j.resmic.2005.11.014
- ↑ Sperandeo P, Cescutti R, Villa R, Di Benedetto C, Candia D, Deho G, Polissi A. Characterization of lptA and lptB, two essential genes implicated in lipopolysaccharide transport to the outer membrane of Escherichia coli. J Bacteriol. 2007 Jan;189(1):244-53. Epub 2006 Oct 20. PMID:17056748 doi:https://dx.doi.org/10.1128/JB.01126-06
- ↑ Sperandeo P, Lau FK, Carpentieri A, De Castro C, Molinaro A, Deho G, Silhavy TJ, Polissi A. Functional analysis of the protein machinery required for transport of lipopolysaccharide to the outer membrane of Escherichia coli. J Bacteriol. 2008 Jul;190(13):4460-9. Epub 2008 Apr 18. PMID:18424520 doi:JB.00270-08
- ↑ Tran AX, Trent MS, Whitfield C. The LptA protein of Escherichia coli is a periplasmic lipid A-binding protein involved in the lipopolysaccharide export pathway. J Biol Chem. 2008 Jul 18;283(29):20342-9. doi: 10.1074/jbc.M802503200. Epub 2008 , May 14. PMID:18480051 doi:https://dx.doi.org/10.1074/jbc.M802503200
- ↑ Sperandeo P, Villa R, Martorana AM, Samalikova M, Grandori R, Deho G, Polissi A. New insights into the Lpt machinery for lipopolysaccharide transport to the cell surface: LptA-LptC interaction and LptA stability as sensors of a properly assembled transenvelope complex. J Bacteriol. 2011 Mar;193(5):1042-53. doi: 10.1128/JB.01037-10. Epub 2010 Dec 17. PMID:21169485 doi:https://dx.doi.org/10.1128/JB.01037-10
- ↑ Schuster M, Brabet E, Oi KK, Desjonquères N, Moehle K, Le Poupon K, Hell S, Gable S, Rithié 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. 2023 May 24;9(21):eadg3683. PMID:37224246 doi:10.1126/sciadv.adg3683
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