7p1c

Crystal structure of E.coli BamA beta-barrel in complex with darobactin BCrystal structure of E.coli BamA beta-barrel in complex with darobactin B

Structural highlights 7p1c is a 2 chain structure with sequence from Escherichia coli O157:H7 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BAMA_ECOLI Part of the outer membrane protein assembly complex, which is involved in assembly and insertion of beta-barrel proteins into the outer membrane. Constitutes, with BamD, the core component of the assembly machinery. Publication Abstract from PubMed There is great need for therapeutics against multidrug-resistant, Gram-negative bacterial pathogens. Recently, darobactin A, a novel bicyclic heptapeptide that selectively kills Gram-negative bacteria by targeting the outer membrane protein BamA, was discovered. Its efficacy was proven in animal infection models of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, thus promoting darobactin A as a promising lead compound. Originally discovered from members of the nematode-symbiotic genus Photorhabdus, the biosynthetic gene cluster (BGC) encoding the synthesis of darobactin A can also be found in other members of the class Gammaproteobacteria. Therein, the precursor peptides DarB to -F, which differ in their core sequence from darobactin A, were identified in silico. Even though production of these analogs was not observed in the putative producer strains, we were able to generate them by mutasynthetic derivatization of a heterologous expression system. The analogs generated were isolated and tested for their bioactivity. The most potent compound, darobactin B, was used for cocrystallization with the target BamA, revealing a binding site identical to that of darobactin A. Despite its potency, darobactin B did not exhibit cytotoxicity, and it was slightly more active against Acinetobacter baumannii isolates than darobactin A. Furthermore, we evaluated the plasma protein binding of darobactin A and B, indicating their different pharmacokinetic properties. This is the first report on new members of this new antibiotic class, which is likely to expand to several promising therapeutic candidates. IMPORTANCE Therapeutic options to combat Gram-negative bacterial pathogens are dwindling with increasing antibiotic resistance. This study presents a proof of concept for the heterologous-expression approach to expand on the novel antibiotic class of darobactins and to generate analogs with different activities and pharmacokinetic properties. In combination with the structural data of the target BamA, this approach may contribute to structure-activity relationship (SAR) data to optimize inhibitors of this essential outer membrane protein of Gram-negative pathogens. Mutasynthetic Production and Antimicrobial Characterization of Darobactin Analogs.,Bohringer N, Green R, Liu Y, Mettal U, Marner M, Modaresi SM, Jakob RP, Wuisan ZG, Maier T, Iinishi A, Hiller S, Lewis K, Schaberle TF Microbiol Spectr. 2021 Dec 22;9(3):e0153521. doi: 10.1128/spectrum.01535-21. Epub , 2021 Dec 22. PMID:34937193 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bam complex 3D structures

spinqualitylabelsall models 7p1c, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image