Octapeptin C1

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Category Antibiotics
Catalog number BBF-03004
CAS 59217-95-7
Molecular Weight 1030.31
Molecular Formula C50H87N13O10

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Description

It is a peptide antibiotic produced by the strain of Bacillus circulans 333-25. It has anti-gram-positive and gram-negative bacteria activity, but no effect on pseudomonas aeruginosa. It inhibits E. coli and Klebsiella pneumoniae with IC50 of 0.95 mg/kg (Mice, subcutaneous).

Specification

Synonyms Antibiotic 333-25; Octapeptin A1, 1-(N(sup 2)-(3-hydroxy-6-methyl-1-oxooctyl)-D-2,4-diaminobutanoic acid)-4-D-phenylalanine-; N2-[N2-(3-Hydroxy-6-methyl-1-oxooctyl)-D-DAB-]cyclo[L-DAB*-L-DAB-D-Phe-L-Leu-L-DAB-L-DAB-L-Leu-]
IUPAC Name N-[4-amino-1-oxo-1-[[6,9,18-tris(2-aminoethyl)-15-benzyl-3,12-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]-3-hydroxy-6-methyloctanamide
Canonical SMILES CCC(C)CCC(CC(=O)NC(CCN)C(=O)NC1CCNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC1=O)CCN)CC2=CC=CC=C2)CC(C)C)CCN)CCN)CC(C)C)O
InChI InChI=1S/C50H87N13O10/c1-7-31(6)13-14-33(64)28-42(65)56-34(15-20-51)44(67)60-38-19-24-55-43(66)39(25-29(2)3)61-46(69)36(17-22-53)57-45(68)35(16-21-52)59-49(72)40(26-30(4)5)62-50(73)41(27-32-11-9-8-10-12-32)63-47(70)37(18-23-54)58-48(38)71/h8-12,29-31,33-41,64H,7,13-28,51-54H2,1-6H3,(H,55,66)(H,56,65)(H,57,68)(H,58,71)(H,59,72)(H,60,67)(H,61,69)(H,62,73)(H,63,70)
InChI Key LXJHAXOSIOZDMJ-UHFFFAOYSA-N

Properties

Appearance Colorless Amorphous Powder
Antibiotic Activity Spectrum Gram-positive bacteria; Gram-negative bacteria
Boiling Point 1383.4°C at 760 mmHg
Melting Point 200°C (dec.)
Density 1.23 g/cm3
Solubility Soluble in Hydrochloric acid

Reference Reading

1. Simulations of octapeptin-outer membrane interactions reveal conformational flexibility is linked to antimicrobial potency
Xukai Jiang, Kai Yang, Bing Yuan, Bin Gong, Lin Wan, Nitin A Patil, James D Swarbrick, Kade D Roberts, Falk Schreiber, Lushan Wang, Tony Velkov, Jian Li J Biol Chem. 2020 Nov 20;295(47):15902-15912. doi: 10.1074/jbc.RA120.014856. Epub 2020 Sep 10.
The octapeptins are lipopeptide antibiotics that are structurally similar to polymyxins yet retain activity against polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant infections. However, the basis of their unique activity is unclear because of the difficulty in generating high-resolution experimental data of the interaction of antimicrobial peptides with lipid membranes. To elucidate these structure-activity relationships, we employed all-atom molecular dynamics simulations with umbrella sampling to investigate the conformational and energetic landscape of octapeptins interacting with bacterial outer membrane (OM). Specifically, we examined the interaction of octapeptin C4 and FADDI-115, lacking a single hydroxyl group compared with octapeptin C4, with the lipid A-phosphoethanolamine modified OM of Acinetobacter baumannii Octapeptin C4 and FADDI-115 both penetrated into the OM hydrophobic center but experienced different conformational transitions from an unfolded to a folded state that was highly dependent on the structural flexibility of their respective N-terminal fatty acyl groups. The additional hydroxyl group present in the fatty acyl group of octapeptin C4 resulted in the molecule becoming trapped in a semifolded state, leading to a higher free energy barrier for OM penetration. The free energy barrier for the translocation through the OM hydrophobic layer was ~72 kcal/mol for octapeptin C4 and 62 kcal/mol for FADDI-115. Our results help to explain the lower antimicrobial activity previously observed for octapeptin C4 compared with FADDI-115 and more broadly improve our understanding of the structure-function relationships of octapeptins. These findings may facilitate the discovery of next-generation octapeptins against polymyxin-resistant Gram-negative 'superbugs.'
2. Solid-Phase Synthesis of Octapeptin Lipopeptides
Karl A Hansford, Zyta M Ziora, Matthew A Cooper, Mark A T Blaskovich Methods Mol Biol. 2020;2103:199-213. doi: 10.1007/978-1-0716-0227-0_13.
Octapeptins are naturally derived cyclic lipopeptide antibiotics with activity against a range of Gram-negative pathogens, including highly resistant strains. Octapeptin C4, an exemplar of the class, was synthesized using a combination of Fmoc solid-phase peptide synthesis (SPPS) and solution-phase cyclization. Utilizing H-L-Leu-2-chlorotrityl resin, peptide couplings were performed using HCTU and collidine in DMF. The linear sequence was terminated by N-acylation with 3-(R)-hydroxydecanoic acid. The residue Dab-2 was orthogonally protected with 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)isovaleryl group (ivDde) to enable selective side-chain deprotection prior to resin cleavage. Resin cleavage was accomplished with hexafluoroisopropanol in DCM, followed by cyclization with diphenylphosphoryl azide (DPPA) and solid sodium bicarbonate in DMF.
3. Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria?
Mark A T Blaskovich, Miranda E Pitt, Alysha G Elliott, Matthew A Cooper Expert Rev Anti Infect Ther. 2018 Jun;16(6):485-499. doi: 10.1080/14787210.2018.1483240. Epub 2018 Jun 26.
The octapeptins are a family of cyclic lipopeptides first reported in the 1970s then largely ignored. At the time, their reported antibiotic activity against polymyxin-resistant bacteria was a curiosity. Today, the advent of widespread drug resistance in Gram-negative bacteria has prompted their 'rediscovery.' The paucity of new antibiotics in the clinical pipeline is coupled with a global spread of increasing antibiotic resistance, particularly to meropenem and polymyxins B and E (colistin). Areas covered: We review the original discovery of octapeptins, their recent first chemical syntheses, and their mode of action, then discuss their potential as a new class of antibiotics to treat extensively drug-resistant (XDR) Gram-negative infections, with direct comparisons to the closely related polymyxins. Expert commentary: Cyclic lipopeptides in clinical use (polymyxin antibiotics) have significant dose-limiting nephrotoxicity inherent to their chemotype. This toxicity has prevented improved polymyxin analogs from progressing to the clinic, and tainted the perception of lipopeptide antibiotics in general. We argue that the octapeptins are fundamentally different from the polymyxins, with a disparate mode of action, spectra of action against MDR and XDR bacteria and a superior preclinical safety profile. They represent early-stage candidates that can help prime the antibiotic discovery pipeline.

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