Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models
| Autor: | William J. Weiss, Sjoerd Nicolaas Wadman, Steven Boakes, Michael J. Dawson, Mary Vinson |
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| Rok vydání: | 2016 |
| Předmět: |
Lung Diseases
Male Methicillin-Resistant Staphylococcus aureus 0301 basic medicine medicine.drug_class 030106 microbiology Antibiotics Microbial Sensitivity Tests Drug resistance Pharmacology medicine.disease_cause Enterococcus faecalis Vancomycin-Resistant Enterococci Microbiology Mice 03 medical and health sciences Bacteriocins In vivo Drug Resistance Multiple Bacterial Drug Discovery medicine Animals Economics Pharmaceutical Lung biology biology.organism_classification Methicillin-resistant Staphylococcus aureus Glycopeptide Anti-Bacterial Agents Disease Models Animal Staphylococcus aureus Area Under Curve Vancomycin Female medicine.drug |
| Zdroj: | The Journal of Antibiotics. 69:850-857 |
| ISSN: | 1881-1469 0021-8820 |
| Popis: | NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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