The calcium-dependent lipopeptide antibiotics: structure, mechanism, &amp; medicinal chemistry

Wood, Thomas M.; Martin, Nathaniel I.

doi:10.1039/c9md00126c

Cited by 52 publications

(57 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the features of some lipopeptide antibiotics is a strict dependence of antimicrobial activity on the presence of calcium ions in the medium. This has led to the creation of a separate class of calcium-dependent lipopeptides (CDAs), with over 40 unique CDAs currently identified ( Wood and Martin, 2019 ). Daptomycin is the first cyclic lipopeptide approved in the United States by the Food and Drug Administration (FDA).…”

Section: Introductionmentioning

confidence: 99%

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

et al. 2020

View full text Add to dashboard Cite

In this work, we report the isolation and detailed functional characterization for the new non-ribosomally synthesized antibiotic 5812-A/C, which was derived from metabolites of Streptomyces roseoflavus INA-Ac-5812. According to its chemical structure, the studied 5812-A/C preliminary is composed of a cyclic peptide part covalently bounded with an arabinose residue. N-terminal amino acid sequencing of the native peptide has identified its partial structure of Leu-Asp-Gly-Ser-Gly and consisting of a Tyr residue that is supposed to have a two-component peptide nature for the molecule studied. However, the structural analysis of the antibiotic complex derived from S. roseoflavus INA-Ac-5812 is still ongoing. The mechanism of action of 5812-A/C was assessed in comparison with its most related analog, the lipopeptide antibiotic daptomycin, given the presence in both antimicrobials of an L-kynurenine amino acid residue. The inhibitory activity of 5812-A/C against Gram-positive bacteria including methicillin-resistant strain of Staphylococcus aureus was similar to daptomycin. The mechanism of action of 5812-A/C was associated with the disruption of membrane integrity, which differs in comparison with daptomycin and is most similar to the antimicrobial membranedisturbing peptides. However, 5812-A/C demonstrated a calcium-dependent mode of action. In addition, unlike daptomycin, 5812-A/C was able to penetrate mature biofilms and inhibit the metabolic activity of embedded S. aureus cells. At the same time, 5812-A/C has no hemolytic activity toward erythrocyte, but possessed weak cytotoxic activity represented by heterochromatin condensation in human buccal epithelium cells. The biological properties of the peptide 5812-A/C suggest its classification as a calcium-dependent antibiotic effective against a wide spectrum of Gram-positive pathogenic bacteria.

show abstract

Section: Introductionmentioning

confidence: 99%

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Three exocyclic amino acids (Trp1, Asn2, Asp3) link the decapeptide core to a decanoyl fatty acid side chain 1,2 . Structurally, DAP resembles a group of acidic lipopeptides, including A54145, friulimicin, tsushimycin and amphomycin 3,4 . Apart from structural features these peptides share a strict requirement of Ca 2+ ions for antimicrobial activity.…”

mentioning

confidence: 99%

Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids

et al. 2020

View full text Add to dashboard Cite

The lipopeptide daptomycin is used as an antibiotic to treat severe infections with grampositive pathogens, such as methicillin resistant Staphylococcus aureus (MRSA) and drugresistant enterococci. Its precise mechanism of action is incompletely understood, and a specific molecular target has not been identified. Here we show that Ca 2+-daptomycin specifically interacts with undecaprenyl-coupled cell envelope precursors in the presence of the anionic phospholipid phosphatidylglycerol, forming a tripartite complex. We use microbiological and biochemical assays, in combination with fluorescence and optical sectioning microscopy of intact staphylococcal cells and model membrane systems. Binding primarily occurs at the staphylococcal septum and interrupts cell wall biosynthesis. This is followed by delocalisation of components of the peptidoglycan biosynthesis machinery and massive membrane rearrangements, which may account for the pleiotropic cellular events previously reported. The identification of carrier-bound cell wall precursors as specific targets explains the specificity of daptomycin for bacterial cells. Our work reconciles apparently inconsistent previous results, and supports a concise model for the mode of action of daptomycin.

show abstract

“…Thus, daptomycin has a distinct mode of action, leading to inhibition of cell wall biosynthesis. 53 Membrane models have proved useful for studies of membrane-active peptides, [54][55][56][57] therefore, we have studied the effects of gausemycin on ion permeability of planar lipid bilayers mimicking bacterial membranes. Results obtained from model membranes (Figure 5D) show that gausemycin B could damage membrane integrity and form ionic channels only at 10×MIC and higher concentrations (Table S27).…”

Section: Resultsmentioning

confidence: 99%

Gausemycins A,B – Cyclic Lipoglycopeptides from Streptomyces Sp.

Tyurin¹,

Alferova²,

Paramonov³

et al. 2021

Preprint

View full text Add to dashboard Cite

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated. The compounds are cyclic peptides with a unique peptide core and several remarkable structural features, including unusual positions of D-amino acids, lack of the Ca2+ -binding Asp-X-Asp-Gly (DXDG) motif, tyrosine glycosylation with arabinose, presence of 2-amino-4-hydroxy-4- phenylbutyric acid (Ahpb) and chlorinated kynurenine (ClKyn), N-acylation of the ornithine side chain. These major components of the peptide antibiotic family have pronounced activity against Gram-positive bacteria. The mechanism of action of gausemycins was explored by a number of methods, showing significant differences compared to glycopeptides and related lipopeptides. For example, gausemycins exhibit no Ca2+ -dependence of antimicrobial activity and induce no pore formation at low concentrations. Moreover, there is no detectable accumulation of cell wall biosynthesis precursors under treatment with gausemycins.

show abstract

The calcium-dependent lipopeptide antibiotics: structure, mechanism, & medicinal chemistry

Abstract: To push back the growing tide of antibacterial resistance the discovery and development of new antibiotics is a must.

Cited by 52 publications

References 64 publications

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

A Novel Peptide Antibiotic Produced by Streptomyces roseoflavus Strain INA-Ac-5812 With Directed Activity Against Gram-Positive Bacteria

Ca2+-Daptomycin targets cell wall biosynthesis by forming a tripartite complex with undecaprenyl-coupled intermediates and membrane lipids

Gausemycins A,B – Cyclic Lipoglycopeptides from Streptomyces Sp.

Contact Info

Product

Resources

About