Beyond vancomycin: recent advances in the modification, reengineering, production and discovery of improved glycopeptide antibiotics to tackle multidrug-resistant bacteria

Hansen, Mathias Henning; Stegmann, Evi; Cryle, Max J.

doi:10.1016/j.copbio.2022.102767

Cited by 15 publications

(16 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8,9 Solution-based synthesis approaches are acceptable for small molecules and short peptides containing arylglycines (Fig. 1) such as arylomycin (6 AAs) 10,11 or vancomycin (7 AAs) 9 but become inefficient for longer sequences such as feglymycin (13 AAs), 12,13 longer type V GPAs 14,15 or the lipoglycodepsipeptide family 16,17 that includes ramoplanin, 18 enduracidin 19 and chersinamycin (17 AAs). 20 In recent years arylglycines have also become a regular inclusion in small molecule SAR campaigns, showing that these residues hold great promise in medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis

Marschall,

Cass,

Prasad

et al. 2024

Chem. Sci.

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis

Marschall,

Cass,

Prasad

et al. 2024

Chem. Sci.

View full text Add to dashboard Cite

show abstract

“…Type II GPAs share a similar crosslinking pattern to the type I GPAs, although this class possesses aromatic amino acids, non-proteinogenic (Hpg) and proteinogenic (Phe) at positions 1 and 3 of the peptide core instead of aliphatic residues [11]. The peptide core of type III GPAs consists exclusively of aromatic amino acids (Hpg 1 -Bht 2 -Dpg 3 -Hpg 4 -Hpg 5 -Bht 6 -Dpg 7 ), which are all crosslinked in contrast to those of type II GPAs. Therefore, type III GPAs contain an additional crosslink compared to type I/II GPAs (4 vs 3) [11].…”

Section: Existing Gpa Classificationmentioning

confidence: 99%

Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics

Gavriilidou

Adámek

Rodler

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Antibiotics have been an essential part of modern medicine since their initial discovery. The continuous exploration of new antibiotic candidates remains a necessity given the increasing emergence of resistance to antimicrobial compounds among pathogens. An important group of last-resort antibiotics, the glycopeptide antibiotics (GPAs), have been studied extensively whilst remaining in clinical use even today. GPAs show diversity in both their structures and biosynthetic gene clusters. Reported GPAs have typically comprised seven amino acid residues, which are highly crosslinked and that are decorated with a variable collection of sugar moieties as well as other modifications. These GPAs, which function through non-covalent binding to the bacterial cell wall precursor lipid II, have been classified into four main types based on their structural characteristics. More recently, atypical GPAs have been identified that differ in both their structure and function, and which have been classified as type V GPAs. Given these differences, we have studied the phylogenetics of all gene sequences related to the biosynthesis of the GPAs, where we observe a clear evolutionary diversification of the lipid II binding GPA classes and the so-called type V GPAs. Here, we suggest the adoption of a phylogeny-driven reclassification and separation of classical lipid II binding GPAs from type V GPAs, which we propose to identify instead as glycopeptide- related peptides (GRPs).

show abstract

“…Actinobacteria produce more than two-thirds of antibiotics used in medicine and agriculture, as well as other specialized metabolites [ 1 ]. One example of these valuable compounds are glycopeptide antibiotics (GPAs) which are last-resort drugs against multidrug-resistant Gram-positive pathogens such as staphylococci, enterococci, and Clostridioides difficile [ 2 , 3 ]. Natural GPAs are produced by fermentation of filamentous actinobacteria mainly from the genera Amycolatopsis, Actinoplanes, and Nonomuraea [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Cross-Talking of Pathway-Specific Regulators in Glycopeptide Antibiotics (Teicoplanin and A40926) Production

et al. 2023

View full text Add to dashboard Cite

Teicoplanin and A40926 (natural precursor of dalbavancin) are clinically relevant glycopeptide antibiotics (GPAs) produced by Actinoplanes teichomyceticus NRRL B-16726 and Nonomuraea gerenzanensis ATCC 39727. Their biosynthetic enzymes are coded within large biosynthetic gene clusters (BGCs), named tei for teicoplanin and dbv for A40926, whose expression is strictly regulated by pathway-specific transcriptional regulators (PSRs), coded by cluster-situated regulatory genes (CSRGs). Herein, we investigated the “cross-talk” between the CSRGs from tei and dbv, through the analysis of GPA production levels in A. teichomyceticus and N. gerenzanensis strains, with knockouts of CSRGs cross-complemented by the expression of heterologous CSRGs. We demonstrated that Tei15* and Dbv4 StrR-like PSRs, although orthologous, were not completely interchangeable: tei15* and dbv4 were only partially able or unable to cross-complement N. gerenzanensis knocked out in dbv4 and A. teichomyceticus knocked out in tei15*, implying that the DNA-binding properties of these PSRs are more different in vivo than it was believed before. At the same time, the unrelated LuxR-like PSRs Tei16* and Dbv3 were able to cross-complement corresponding N. gerenzanensis knocked out in dbv3 and A. teichomyceticus knocked out in tei16*. Moreover, the heterologous expression of dbv3 in A. teichomyceticus led to a significant increase in teicoplanin production. Although the molecular background of these events merits further investigations, our results contribute to a deeper understanding of GPA biosynthesis regulation and offer novel biotechnological tools to improve their production.

show abstract

Beyond vancomycin: recent advances in the modification, reengineering, production and discovery of improved glycopeptide antibiotics to tackle multidrug-resistant bacteria

Cited by 15 publications

References 57 publications

Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis

Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis

Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics

Cross-Talking of Pathway-Specific Regulators in Glycopeptide Antibiotics (Teicoplanin and A40926) Production

Contact Info

Product

Resources

About