Synthesis and biological evaluation of lipophilic teicoplanin pseudoaglycon derivatives containing a substituted triazole function

Szűcs, Zsolt; Csávás, Magdolna; Rőth, Erzsébet; Borbás, Anikó; Batta, Gyula; Perret, Florent; Ostorházi, Eszter; Szatmári, Réka; Vanderlinden, Evelien; Naesens, Lieve; Herczegh, Pál

doi:10.1038/ja.2016.80

Cited by 21 publications

(27 citation statements)

References 27 publications

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“…It is of great concern that VanZ orthologs were active against TEI pseudoaglycon derivatives, which represent the newest generation of lipoglycopeptides with promising in vitro activity against glycopeptide-resistant strains (Szucs et al, 2017). Similar to ORI, these derivatives show equal competition with FL-TEI and FL-VAN for binding to S. aureus cells, and this result correlates with their activity against vanHAXmediated resistance (Vimberg et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Teicoplanin, vancomycin, oritavancin, and chloramphenicol (Sigma-Aldrich, Germany); dalbavancin (MedChemExpress, Sweden); MA79 (Csávás et al, 2015), ERJ390 (Pintér et al, 2009), and SZZS-12 (Szucs et al, 2017); carbenicillin, gentamicin and erythromycin (Duchefa Biochemie, Netherland); vancomycin BODIPY-FL conjugate (Thermo Fisher Scientific, Germany) and fluorescently labeled teicoplanin (Vimberg et al, 2019).…”

Section: Antibioticsmentioning

confidence: 99%

“…The ability of the E. faecium vanZ Tei and vanZ g paralogs to confer resistance to glycopeptide antibiotics was tested in S. aureus, which naturally does not encode any proteins of the VanZ superfamily. In particular, we determined the susceptibility of S. aureus RN4220 expressing vanZ Tei and vanZ g to the clinically used glycopeptide antibiotic vancomycin (VAN); the lipoglycopeptide antibiotics teicoplanin (TEI), oritavancin (ORI), and dalbavancin (DALB); and three experimental lipoglycopeptide antibiotics derived from teicoplanin pseudoaglycone: MA79 (Csávás et al, 2015), ERJ390 (Pintér et al, 2009) and SZZS-12 (Szucs et al, 2017; Figure 1). In addition, the non-glycopeptide antibiotics carbenicillin (CARB, cell wall-targeting) gentamicin (GEN, 30S ribosometargeting) and erythromycin (ERY, 50S ribosome-targeting) were used as controls.…”

Section: Glycopeptide Antibioticsmentioning

confidence: 99%

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VanZ Reduces the Binding of Lipoglycopeptide Antibiotics to Staphylococcus aureus and Streptococcus pneumoniae Cells

et al. 2020

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vanZ, a member of the VanA glycopeptide resistance gene cluster, confers resistance to lipoglycopeptide antibiotics independent of cell wall precursor modification by the vanHAX genes. Orthologs of vanZ are present in the genomes of many clinically relevant bacteria, including Enterococcus faecium and Streptococcus pneumoniae; however, vanZ genes are absent in Staphylococcus aureus. Here, we show that the expression of enterococcal vanZ paralogs in S. aureus increases the minimal inhibitory concentrations of lipoglycopeptide antibiotics teicoplanin, dalbavancin, oritavancin and new teicoplanin pseudoaglycone derivatives. The reduction in the binding of fluorescently labeled teicoplanin to the cells suggests the mechanism of VanZ-mediated resistance. In addition, using a genomic vanZ gene knockout mutant of S. pneumoniae, we have shown that the ability of VanZ proteins to compromise the activity of lipoglycopeptide antibiotics by reducing their binding is a more general feature of VanZ-superfamily proteins.

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Section: Discussionmentioning

confidence: 99%

Section: Antibioticsmentioning

confidence: 99%

Section: Glycopeptide Antibioticsmentioning

confidence: 99%

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VanZ Reduces the Binding of Lipoglycopeptide Antibiotics to Staphylococcus aureus and Streptococcus pneumoniae Cells

et al. 2020

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“…Synthesis of 3 27 and 7-9 has been published recently. 28 Lipoic acid derivatives 1 and 2 were prepared from N-acetylglucosaminyl teicoplanin aglycon 29 10 by simple acylation reactions with hydroxysuccinimide active esters 11 and 12 24 (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycin- and teicoplanin-resistant enterococci

et al. 2017

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A selection of nine derivatives of teicoplanin pseudoaglycon were tested in vitro against clinical vancomycin-resistant Enterococcus strains possessing vanA, vanB or both genes. The bacteria were characterized by PCR for the identification of their resistance genes. The tested compounds contain lipoic acid, different carbohydrates and aryl groups as lipophilic moieties. About one-third of the teicoplanin-resistant strains were shown to be susceptible to one or more of the glycopeptide derivatives.

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“…Some of these N -terminal derivatives 23 (e.g., triazole substituted with phenol or naphthol) showed modest improvements in activity against VRE strains, though toxicity against mammalian cells also increased. 127,128 …”

Section: New Glycopeptide Derivativesmentioning

confidence: 99%

Developments in Glycopeptide Antibiotics

et al. 2018

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Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multidrug resistant (MDR) S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) together causing 20-fold more infections than all MDR Gram-negative infections combined, further improvements are desirable to ensure the Gram-positive armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the past decade via total syntheses, semisynthetic modifications of natural products, or biological engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles, and no reported preclinical toxicity; some may be suitable for formal preclinical development. The natural product monobactam, cephalosporin, and β-lactam antibiotics all spawned multiple generations of commercially and clinically successful semisynthetic derivatives. Similarly, next-generation glycopeptides are now technically well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.

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Synthesis and biological evaluation of lipophilic teicoplanin pseudoaglycon derivatives containing a substituted triazole function

Cited by 21 publications

References 27 publications

VanZ Reduces the Binding of Lipoglycopeptide Antibiotics to Staphylococcus aureus and Streptococcus pneumoniae Cells

VanZ Reduces the Binding of Lipoglycopeptide Antibiotics to Staphylococcus aureus and Streptococcus pneumoniae Cells

Lipophilic teicoplanin pseudoaglycon derivatives are active against vancomycin- and teicoplanin-resistant enterococci

Developments in Glycopeptide Antibiotics

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