Production of hybrid glycopeptide antibiotics in vitro and in Streptomyces toyocaensis
Patricia J. SolenbergPatti MatsushimaDouglas R. StackStephen C. WilkieR. C. ThompsonRichard H. Baltz
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Teicoplanin
Glycopeptide antibiotic
LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin- and teicoplanin-resistant enterococci of < or = 4 micrograms/ml for 50% of isolates and < or = 16 micrograms/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 micrograms/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.
Teicoplanin
Glycopeptide antibiotic
Vancomycin-Resistant Enterococci
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Glycopeptide antibiotics, vancomycin and teicoplanin, inhibit cell wall synthesis in Gram-positive bacteria by interacting with peptidoglycan D-Ala-D-Ala peptide stem termini of the pentapeptide side chains of the peptidoglycan precursors. In glycopeptide-resistant bacteria, multiresistance poses major therapeutic problems. New potent antibacterial agents are needed to combat these resistance problems, resulting in the explosion of novel glycopeptides in recent years. The glycosylation patterns of glycopeptides and the chemical modifications of the glycosyl moieties greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. Considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. This review provides an overview of the chemistry, the antimicrobial activity, the pharmacokinetics and the toxicology of teicoplanin and other glycopeptide antibiotic derivatives.
Teicoplanin
Glycopeptide antibiotic
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Teicoplanin
Glycopeptide antibiotic
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Teicoplanin
Glycopeptide antibiotic
Enterococcus faecalis
Enterococcus faecium
Amide
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Teicoplanin is a glycopeptide antibiotic that has proven efficacy against Gram‐positive bacteria and is in clinical trials. It is distinguished from vancomycin‐type glycopeptides antibiotics by side chain modifications, which have been shown to contribute to its improved efficacy and superior pharmacokinetic profile. Our research aims to study the biosynthetic mechanisms of teicoplanin, which will likely lead to the development of new glycopeptide derivatives. Here we present high resolution crystal structures of several enzymes that modify teicoplanin side chains during its biosynthesis. The structures provide insights into the active residues of these enzymes and suggest possible mechanisms of modifying glycopeptides antibiotics.
Teicoplanin
Glycopeptide antibiotic
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The antibiotic glycopeptide class, of which vancomycin is the original compound, has received due attention over the past few decades in search of antibiotics to overcome resistances developed by bacteria. Crucial for the understanding and further development of glycopeptides that possess desired antibacterial effects is the determination of their conformational behavior, as this sheds light on the mechanism of action of the compound. Among others, vibrational optical activity (VOA) techniques (vibrational circular dichroism and Raman optical activity) can be deployed for this, but the question remains to what extent these spectroscopic techniques can provide information concerning the molecular class under investigation. This contribution takes the last hurdle in the search for the capabilities of the VOA techniques in the conformational analysis of the antibiotic glycopeptide class by extending research that was previously conducted for vancomycin toward its three derivatives: oritavancin, dalbavancin, and teicoplanin. The principal information that can be drawn from VOA spectra is the conformation of the rigid cyclic parts of the glycopeptides and the aromatic rings that are part hereof. The addition or removal of carbohydrates does not induce noticeable VOA spectral responses, preventing the determination of the conformation they adopt.
Teicoplanin
Glycopeptide antibiotic
Dalbavancin
Raman optical activity
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Glycopeptide antibiotics are clinically important as a second-line therapy for the treatment for nosocomial infections caused by Gram-positive pathogens. A universal mode of action for glycopeptide antibiotics is to target the terminal residues, d-Alanyl-d-Alanine on the cell wall peptidoglycan intermediate lipid II, arresting the later stages of peptidoglycan biosynthesis. This weakens the cell wall, making it susceptible to rupture. A general resistance mechanism for glycopeptide antibiotics requires the core genes, vanRSHAX, that detect the presence of a glycopeptide (VanS) and upregulate genes (VanR) which orchestrate the remodelling of d-Ala-d-Ala on lipid II to d-Ala-d-Lactate (VanHAX). Glycopeptide affinity for lipid II is reduced by 1000-fold and biological activity impaired. Our previous study has shown that altering the termini of peptidoglycan precursors by VanHAX action was not sufficient for the resistance of the glycopeptide teicoplanin in S. coelicolor , which is instead mediated mainly by VanJ. Using RNA-seq, this study is designed to understand how the adaptive response in an S. coelicolor wild type (M600) and a vanJ mutant strain differ after exposure to teicoplanin. We have also compared these data with available data on the cell wall targeting antibiotics vancomycin, bacitracin and moenoymycin. By doing so, we aim to gain insight into the molecular basis of the improved activity of teicoplanin over vancomycin as well as identify novel cellular targets of teicoplanin which can help inform the design of future glycopeptides with desirable therapeutic properties.
Teicoplanin
Glycopeptide antibiotic
Lipid II
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The structure of the two factors of the novel glycopeptide antibiotic A40926 have been determined using a combination of FAB-MS, GC-MS and 1H n.m.r. studies. A40926 Is a member of the vancomycin family of antibiotics and is structurally related to teicoplanin, A35512B and aridicin.
Teicoplanin
Glycopeptide antibiotic
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The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) ≤ 4 μg/mL] and had better activity against Gram-positive strains sensitive to glycopeptides than against GRE. Extensive degradation of the glycopeptide framework in amides of 7 and 8 led to a decrease of anti-GRE activity (MIC = 16−64 μg/mL), and for these derivatives MIC values for bacterial strains sensitive and resistant to glycopeptides were very close. These results suggest that in sensitive bacteria two mechanisms of action are operating for the hydrophobic derivatives of glycopeptide antibiotics with the nondamaged peptide coreinteraction with the d-Ala-d-Ala moiety and the inhibition of bacterial membrane bound enzymatic reactions, whereas for GRE lacking the d-Ala-d-Ala fragment, only the second mechanism is operating. It appears that a minimal glycopeptide core is required for activity, and that more extensive degradation results in a serious decrease of antibacterial activity.
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Glycopeptide antibiotic
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The in vitro activity of SK&F 104662, a new glycopeptide antibiotic, against gram-positive bacteria was evaluated. Activity was comparable to those of teicoplanin and vancomycin against most organisms. SK&F 104662 inhibited diphtheroids at concentrations of less than or equal to 0.5 microgram/ml. Addition of human serum to the test medium lowered the inhibitory activity of this glycopeptide against some organisms by as much as eightfold.
Glycopeptide antibiotic
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