Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors
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 inh...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/4/633 |
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| author | Nakita Reddy Letisha Girdhari Mbongeni Shungube Arnoldus C. Gouws Byron K. Peters Kamal K. Rajbongshi Sooraj Baijnath Sipho Mdanda Thandokuhle Ntombela Thilona Arumugam Linda A. Bester Sanil D. Singh Anil Chuturgoon Per I. Arvidsson Glenn E. M Maguire Hendrik G. Kruger Thavendran Govender Tricia Naicker |
| author_facet | Nakita Reddy Letisha Girdhari Mbongeni Shungube Arnoldus C. Gouws Byron K. Peters Kamal K. Rajbongshi Sooraj Baijnath Sipho Mdanda Thandokuhle Ntombela Thilona Arumugam Linda A. Bester Sanil D. Singh Anil Chuturgoon Per I. Arvidsson Glenn E. M Maguire Hendrik G. Kruger Thavendran Govender Tricia Naicker |
| author_sort | Nakita Reddy |
| collection | DOAJ |
| description | 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 (K<i><sub>i</sub></i><sub>app</sub>) 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 log<sub>10</sub> reduction in <i>K. pneumoniae</i> NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI). |
| first_indexed | 2024-03-11T05:18:57Z |
| format | Article |
| id | doaj.art-72015b20994f46ae9bddd7b2baa61e04 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T05:18:57Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-72015b20994f46ae9bddd7b2baa61e042023-11-17T18:01:46ZengMDPI AGAntibiotics2079-63822023-03-0112463310.3390/antibiotics12040633Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase InhibitorsNakita Reddy0Letisha Girdhari1Mbongeni Shungube2Arnoldus C. Gouws3Byron K. Peters4Kamal K. Rajbongshi5Sooraj Baijnath6Sipho Mdanda7Thandokuhle Ntombela8Thilona Arumugam9Linda A. Bester10Sanil D. Singh11Anil Chuturgoon12Per I. Arvidsson13Glenn E. M Maguire14Hendrik G. Kruger15Thavendran Govender16Tricia Naicker17Catalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaSchool of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaSchool of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaDepartment of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville Campus, Durban 3629, South AfricaSchool of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaDepartment of Chemistry, University of Zululand, Private Bag X1001, KwaDlangezwa 3886, South AfricaCatalysis and Peptide Research Unit, University of KwaZulu-Natal, Durban 4001, South AfricaVirulent 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 (K<i><sub>i</sub></i><sub>app</sub>) 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 log<sub>10</sub> reduction in <i>K. pneumoniae</i> NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).https://www.mdpi.com/2079-6382/12/4/633metallo-β-lactamasesCarbapenem resistant <i>Enterobacterales</i>cyclic amino acidic chelatorBP2murine thigh infection model |
| spellingShingle | Nakita Reddy Letisha Girdhari Mbongeni Shungube Arnoldus C. Gouws Byron K. Peters Kamal K. Rajbongshi Sooraj Baijnath Sipho Mdanda Thandokuhle Ntombela Thilona Arumugam Linda A. Bester Sanil D. Singh Anil Chuturgoon Per I. Arvidsson Glenn E. M Maguire Hendrik G. Kruger Thavendran Govender Tricia Naicker Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors Antibiotics metallo-β-lactamases Carbapenem resistant <i>Enterobacterales</i> cyclic amino acidic chelator BP2 murine thigh infection model |
| title | Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors |
| title_full | Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors |
| title_fullStr | Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors |
| title_full_unstemmed | Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors |
| title_short | Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors |
| title_sort | neutralizing carbapenem resistance by co administering meropenem with novel β lactam metallo β lactamase inhibitors |
| topic | metallo-β-lactamases Carbapenem resistant <i>Enterobacterales</i> cyclic amino acidic chelator BP2 murine thigh infection model |
| url | https://www.mdpi.com/2079-6382/12/4/633 |
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