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- Reddy, N, et al.
(författare)
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Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
- 2023
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Ingår i: Antibiotics (Basel, Switzerland). - : MDPI AG. - 2079-6382. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).
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| 4. |
- Reddy, N, et al.
(författare)
-
Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
- 2023
-
Ingår i: Antibiotics (Basel, Switzerland). - : MDPI AG. - 2079-6382. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).
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- Rodgers, Timothy F.M., et al.
(författare)
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Novel Bayesian Method to Derive Final Adjusted Values of Physicochemical Properties : Application to 74 Compounds
- 2021
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55:18, s. 12302-12316
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Tidskriftsartikel (refereegranskat)abstract
- Accurate values of physicochemical properties are essential for screening semivolatile organic compounds for human and environmental hazard and risk. In silico approaches for estimation are widely used, but the accuracy of these and measured values can be difficult to ascertain. Final adjusted values (FAVs) harmonize literature-reported measurements to ensure consistency and minimize uncertainty. We propose a workflow, including a novel Bayesian approach, for estimating FAVs that combines measurements using direct and indirect methods and in silico values. The workflow was applied to 74 compounds across nine classes to generate recommended FAVs (FAVRs). Estimates generated by in silico methods (OPERA, COSMOtherm, EPI Suite, SPARC, and polyparameter linear free energy relationships (pp-LFER) models) differed by orders of magnitude for some properties and compounds and performed systematically worse for larger, more polar compounds. COSMOtherm and OPERA generally performed well with low bias although no single in silico method performed best across all compound classes and properties. Indirect measurement methods produced highly accurate and precise estimates compared with direct measurement methods. Our Bayesian method harmonized measured and in silico estimated physicochemical properties without introducing observable biases. We thus recommend use of the FAVRs presented here and that the proposed Bayesian workflow be used to generate FAVRs for SVOCs beyond those in this study.
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