Total chemical synthesis of glycocin F and analogues: <i>S</i>-glycosylation confers improved antimicrobial activity

Amso, Zaid; Bisset, Sean W.; Yang, Sung‐Hyun; Harris, Paul W. R.; Wright, Tom H.; Navo, Claudio D.; Patchett, Mark L.; Norris, Gillian E.; Brimble, Margaret A.

doi:10.1039/c7sc04383j

Cited by 43 publications

(39 citation statements)

References 18 publications

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“…11,12 Its activity can be counteracted by adding GlcNAc to the growth medium, but not other sugars, 11 and recent studies showed that it is the GlcNAc on the interhelical loop that appears responsible for its activity. 13,14 A main difference in addition to glycocin F carrying two GlcNAc and sublancin only one Glc is that glycocin F is bacteriostatic, and sublancin is bactericidal. 8,11 Glycocin F is thought to interact with the GlcNAc PTS through a currently unknown mechanism with the C-terminal GlcNAc possibly responsible for its specificity.…”

Section: Resultsmentioning

confidence: 99%

“…Radioactivity was then determined on a scintillation counter (PerkinElmer Tri-Carb 2910 TR). The radiolabels and their corresponding positive and negative antibiotic controls were: Cell wall: [ 14 The procedure was the same as that listed above, except two concentrations (0.1% and 0.01%) of glucose were added in the refined LB medium to grow B. subtilis 168 ΔSPβ. A final concentration of 0.8 μCi/mL [ 14 C]-glucose (PerkinElmer, NEC042X050UC) was added.…”

Section: Macromolecular Synthesis Assaysmentioning

confidence: 99%

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Investigations into the Mechanism of Action of Sublancin

Biswas

Gonzalo

et al. 2018

ACS Infect. Dis.

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Antimicrobial resistance is a global threat that poses a rising concern. One underlying challenge is the limited number of targets in bacteria affected by the current pool of antibiotics. To potentially help find new targets, we studied a member of the class of antimicrobial natural products named glycocins. We examined the mode of action of sublancin, which contains an unusual and essential glucosylated Cys residue, by monitoring macromolecular synthesis. Sublancin negatively affected DNA replication, transcription, and translation without affecting cell wall biosynthesis. In addition, we confirmed that the presence of the PTS sugar glucose in the medium negatively impacted antimicrobial activity of sublancin. Additionally, sublancin analogues carrying different sugars retained their antimicrobial activity regardless of which sugar was attached to the peptide or the carbon source used. These data suggest a novel mechanism upstream of transcription and translation and are consistent with previous studies suggesting that the glucose uptake system is involved.

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Section: Resultsmentioning

confidence: 99%

Section: Macromolecular Synthesis Assaysmentioning

confidence: 99%

Investigations into the Mechanism of Action of Sublancin

Biswas

Gonzalo

et al. 2018

ACS Infect. Dis.

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“…The sactibiotic subtilosin A displays rare sulphur to α-carbon bonds involving D-amino acid residues [46] and also has a head-to-tail cyclic backbone. Finally, glycocins are disulfide-bridged peptides that have sugar moieties linked to an additional cysteine residue, which are important for their antimicrobial activity [47]. The structure of sublancin 168 exhibits two α-helical segments that are linked by two disulfide bonds.…”

Section: Insert Boxmentioning

confidence: 99%

The Vast Structural Diversity of Antimicrobial Peptides

Koehbach

Craik

2019

Trends in Pharmacological Sciences

194

138

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Antimicrobial peptides (AMPs) occur in all kingdoms of life and are integral to host defense. They have diverse structures and target a variety of organisms, both by non-specific membrane interactions or via specific targets. Here we discuss the structures of AMPs from the four main classes currently recognized, i.e. peptides with (i) α-helical; (ii) β-sheet; (iii) αβ; and (iv) non-αβ elements as well as the growing pool of complex topologies including various post-translational modifications. We propose to group these latter peptides into a fifth class of AMPs. Such peptides exhibit high stability and amenability to chemical engineering, making them of interest for the development of novel antimicrobial agents. Advances and challenges in the development of these peptides towards therapeutic leads are presented. AMPsa diverse, but unifying strategy for defense Antimicrobial resistance has been identified as a major threat to public health and without immediate and global action the world is headed for a dangerous post-antibiotic era [1]. Thus, there is an urgent need for the development of novel antibiotic drugs to treat infectious diseases. In contrast to the rising numbers of multi drug resistant pathogens the rate of discovery of novel drug candidates is dwindling [2]. In this regard antimicrobial peptides (AMP) are a promising class of bioactive compounds that have attracted increasing attention over recent years. Their broad spectrum of activities extends beyond the killing of bacteria and fungi, with several AMPs also exhibiting antiviral [3], antiparasitic [4] or anticancer activities [5]. Furthermore, their multifaceted mechanisms-of-action potentially reduce their susceptibility to suffer from microbial resistance [6]. Starting in the 1980s, at a time when the numbers of novel antibacterial agents started to drop, the field of AMP research gained momentum when several novel examples were independently discovered across different species. These included peptides such as the cecropins from insects [7], the magainins from amphibians [8] and the mammalian defensins [9] to name a few. Since then a plethora of AMPs has been identified from all kingdoms of life, from bacteria to fungi to plants and animals. It is not only evident that these peptides play an integral part of an organism's innate defense machinery, but their variety also makes them a rich source for the discovery of potential novel drug leads. Their distribution among virtually all living organisms is complemented by their structural variety and range of antimicrobial activities. In this review we highlight this vast structural diversity of antimicrobial peptides. As well as providing a brief overview of the structures of well-known classes of AMPs, we introduce the growing class of structurally complex AMP topologies, in particular, cyclic and cysteine-rich defense peptides. We discuss recent progress and challenges in the characterization and development of peptide-based antibacterial molecules. 3 Structural classes of antimicrobial peptides Th...

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“…As a representative example, in 2018, Amso et al. reported the total synthesis of glycocin F (GccF; 14 ), which is a diglycosylated 43‐residue compound that contains two disulfide bridges between the residues Cys 5 –Cys 28 and Cys 12 –Cys 21 , forming two macrocycles . Total synthesis was achieved by using a native chemical ligation strategy .…”

Section: Bacterial Antimicrobial Cyclopeptidesmentioning

confidence: 99%

“…As ar epresentative example, in 2018, Amso et al reported the total synthesis of glycocin F ( GccF; 14), which is ad iglycosylated 43-residue compound that containst wo disulfide bridges between the residues Cys 5 -Cys 28 and Cys 12 -Cys 21 ,form-ing two macrocycles. [152] To tal synthesis was achieved by using an ative chemicall igation strategy. [153] The fully deprotected linear precursor was oxidized under optimal conditions by using 2mm cysteine, 0.25 mm cystine, and 0.1 mm EDTA in 1.5 m guanidine hydrochloride (Gn·HCl;p H8.2) at 4 8Cf or 16 h to afford the cyclized glycocin F(Scheme 4).…”

Section: Wwwchemmedchemorgmentioning

confidence: 99%

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

et al. 2018

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In the last few decades, peptides have been victorious over small molecules as therapeutics due to their broad range of applications, high biological activity, and high specificity. However, the main challenges to overcome if peptides are to become effective drugs is their low oral bioavailability and instability under physiological conditions. Cyclic peptides play a vital role in this context because they show higher stability under physiological conditions, higher membrane permeability, and greater oral bioavailability than that of their corresponding linear analogues. In this regard, cyclic antimicrobial peptides (AMPs) have gained considerable attention in the field of novel antibiotic development. Bacterial strains produce cyclic AMPs through two pathways: ribosomal and nonribosomal. This review provides an overview of the chemical classification of cyclic AMPs isolated from bacteria, and provides a description of their biological activity and mode of action.

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Total chemical synthesis of glycocin F and analogues: S-glycosylation confers improved antimicrobial activity

Abstract: Replacing the O-linked saccharide in the bacteriocin glycocin F with an S-linked version results in a peptidomimetic that increases the bacteriostatic effect.

Cited by 43 publications

References 18 publications

Investigations into the Mechanism of Action of Sublancin

Investigations into the Mechanism of Action of Sublancin

The Vast Structural Diversity of Antimicrobial Peptides

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

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