Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains

Groesen, Emma van; Slingerland, Cornelis J.; Innocenti, Paolo; Mihajlovic, Milos; Masereeuw, Rosalinde; Martin, Nathaniel I.

doi:10.1021/acsinfecdis.1c00318

Cited by 20 publications

(22 citation statements)

References 51 publications

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“…Negative controls containing dissolution solvents at a final concentration of 2% or polymyxin B at 0.49 µg/mL were simultaneously carried out, and the growth was compared to the viability control, which contained only a culture medium. In order to demonstrate that permeabilization is occurring, vancomycin, whose target is the PG precursor lipid II present in E. coli [ 42 ], was used as a control [ 43 ]. The large size of this glycopeptide antibiotic avoids its entrance into Gram-negative bacteria [ 44 ], while the addition of polymyxin B overcomes this inconvenience [ 45 ].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

et al. 2021

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Enzymes MurA and MurF, involved in bacterial cell wall synthesis, have been validated as targets for the discovery of novel antibiotics. A panel of plant-origin antibacterial diterpenes and synthetic analogs derived therefrom were investigated for their inhibitory properties on these enzymes from Escherichia coli and Staphylococcus aureus. Six compounds were proven to be effective for inhibiting MurA from both bacteria, with IC50 values ranging from 1.1 to 25.1 µM. To further mechanistically investigate the nature of binding and to explain the activity, these compounds were docked into the active site of MurA from E. coli. The aromatic ring of the active compounds showed a T-shaped π–π interaction with the phenyl ring of Phe328, and at least one hydrogen bond was formed between the hydroxy groups and Arg120 and/or Arg91. The results disclosed here establish new chemical scaffolds for the development of novel entities targeting MurA as potential antibiotics to combat the threat of pathogenic bacteria, particularly resistant strains.

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Section: Methodsmentioning

confidence: 99%

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

et al. 2021

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“… 281 , 282 In addition, we also do not cover reports describing systems where an OM-perturbing motif like PMBN is covalently linked to another antibiotic as a means of enhancing anti-Gram-negative activity. 39 , 283 − 285 …”

Section: Antibiotic-derived Synergistsmentioning

confidence: 99%

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Wesseling

Martin

2022

ACS Infect. Dis.

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New approaches to target antibacterial agents toward Gram-negative bacteria are key, given the rise of antibiotic resistance. Since the discovery of polymyxin B nonapeptide as a potent Gram-negative outer membrane (OM)-permeabilizing synergist in the early 1980s, a vast amount of literature on such synergists has been published. This Review addresses a range of peptide-based and small organic compounds that disrupt the OM to elicit a synergistic effect with antibiotics that are otherwise inactive toward Gram-negative bacteria, with synergy defined as a fractional inhibitory concentration index (FICI) of <0.5. Another requirement for the inclusion of the synergists here covered is their potentiation of a specific set of clinically used antibiotics: erythromycin, rifampicin, novobiocin, or vancomycin. In addition, we have focused on those synergists with reported activity against Gram-negative members of the ESKAPE family of pathogens namely, Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae , and/or Acinetobacter baumannii . In cases where the FICI values were not directly reported in the primary literature but could be calculated from the published data, we have done so, allowing for more direct comparison of potency with other synergists. We also address the hemolytic activity of the various OM-disrupting synergists reported in the literature, an effect that is often downplayed but is of key importance in assessing the selectivity of such compounds for Gram-negative bacteria.

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“…The search for new glycopeptide antibiotics with improved chemotherapeutic properties is a current focus of antimicrobial drug development [1,[8][9][10]. This is due to three main factors: the spreading of strain resistance to natural glycopeptides, restrictions for the indication of use due to their short half-life, rapid excretion, low accumulation in certain tissues, and the presence of side effects [11].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

et al. 2022

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Glycopeptide antibiotics have side effects that limit their clinical use. In view of this, the development of glycopeptides with improved chemotherapeutic properties remains the main direction in the search for new antibacterial drugs. The objective of this study was to evaluate the toxicological characteristics of new semi-synthetic glycopeptide flavancin. Acute and chronic toxicity of antibiotic was evaluated in Wistar rats. The medium lethal dose (LD50) and the maximum tolerated doses (MTD) were calculated by the method of Litchfield and Wilcoxon. In the chronic toxicity study, the treatment regimen consisted of 15 daily intraperitoneal injections using two dosage levels: 6 and 10 mg/kg/day. Total doses were equivalent to MTD or LD50 of flavancin, respectively. The study included assessment of the body weight, hematological parameters, blood biochemical parameters, urinalysis, and pathomorphological evaluation of the internal organs. The results of the study demonstrated that no clinical-laboratory signs of toxicity were found after 15 daily injections of flavancin at a total dose close to the MTD or LD50. The pathomorphological study did not reveal any lesions on the organ structure of animals after low-dose administration of flavancin. Thus, flavancin favorably differs in terms of toxicological properties from the glycopeptides currently used in the clinic.

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Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced Potency against Gram-Negative Strains

Cited by 20 publications

References 51 publications

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

Inhibition of MurA Enzyme from Escherichia coli and Staphylococcus aureus by Diterpenes from Lepechinia meyenii and Their Synthetic Analogs

Synergy by Perturbing the Gram-Negative Outer Membrane: Opening the Door for Gram-Positive Specific Antibiotics

Evaluation of Toxic Properties of New Glycopeptide Flavancin on Rats

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