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Neutralizing Carbap...
Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
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Reddy, N (author)
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Girdhari, L (author)
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Shungube, M (author)
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Gouws, AC (author)
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Peters, BK (author)
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Rajbongshi, KK (author)
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Baijnath, S (author)
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Mdanda, S (author)
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Ntombela, T (author)
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Arumugam, T (author)
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Bester, LA (author)
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Singh, SD (author)
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Chuturgoon, A (author)
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- Arvidsson, PI (author)
- Karolinska Institutet
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Maguire, GEM (author)
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Kruger, HG (author)
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Govender, T (author)
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Naicker, T (author)
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(creator_code:org_t)
- 2023-03-23
- 2023
- English.
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In: Antibiotics (Basel, Switzerland). - : MDPI AG. - 2079-6382. ; 12:4
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https://doi.org/10.3...
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Abstract
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- 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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- ref (subject category)
- art (subject category)
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- By the author/editor
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Reddy, N
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Girdhari, L
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Shungube, M
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Gouws, AC
-
Peters, BK
-
Rajbongshi, KK
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show more...
-
Baijnath, S
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Mdanda, S
-
Ntombela, T
-
Arumugam, T
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Bester, LA
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Singh, SD
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Chuturgoon, A
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Arvidsson, PI
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Maguire, GEM
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Kruger, HG
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Govender, T
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Naicker, T
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show less...
- Articles in the publication
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Antibiotics (Bas ...
- By the university
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Karolinska Institutet