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Peer-reviewedCC BY-NC-NDACS infectious diseases

JDB-1-200, an Atypically Modified Carbapenem with Standalone In Vitro Activity against KPC-Producing Enterobacterales.

  • Taariq Hassan1
  • Svanik Jaikumar1
  • Diya Patel1
  • Pojun Quan1
  • Maidileyvis Castro Cabello1
  • Jonathan E Cox1
  • Md Mahbub Kabir Khan1
  • James Spencer2
  • Catherine L Tooke3
  • John D Buynak1
  1. 1Department of Chemistry, Southern Methodist University, Dallas, Texas75275, United States.
  2. 2School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, BristolBS8 1TD, U.K.
  3. 3Department of Life Sciences and Centre of Evolution, University of Bath, Claverton Down, BathBA2 7AY, U.K.
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Abstract

Carbapenem-resistant Enterobacterales (CRE), including Escherichia coli and Klebsiella pneumoniae are increasingly common pathogens. Resistance in CRE is often associated with production of K. pneumoniae (KPC) carbapenemases. We report a structurally modified meropenem derivative, JDB-1-200 (i.e., 8-epi-meropenem, in which the stereochemistry of the C8 hydroxyl is inverted), displaying enhanced activity relative to meropenem against KPC-producing CRE. JDB-1-200 alone displayed superior activity (MICs of 0.5 to 1 mg/L, compared with >8 mg/L for meropenem) against several clinically relevant Enterobacterales, including KPC-producing K. pneumoniae and Citrobacter freundii. Crystallographic analysis of JDB-1-200 complexes with the E166Q deacylation-deficient KPC-2 mutant, compared with an analogous meropenem (8R-hydroxyl) complex, indicates that the improvement arises from the JDB 8S-hydroxyl group acting as a hydrogen-bond donor to the hydrolytic water, slowing acyl-enzyme hydrolysis, with similar interactions observed in a CTX-M-15:JDB-1-200 complex. Kinetic inhibition data for KPC-2 and CTX-M-15 indicate that JDB-1-200 could be used alone or alongside a β-lactamase inhibitor for effective CRE treatment.

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Cite

BibTeXRIS
BibTeX
@article{hassan2026jdb1200,
  title = {{JDB-1-200, an Atypically Modified Carbapenem with Standalone In Vitro Activity against KPC-Producing Enterobacterales.}},
  author = {Taariq Hassan and Svanik Jaikumar and Diya Patel and Pojun Quan and Maidileyvis Castro Cabello and Jonathan E Cox and Md Mahbub Kabir Khan and James Spencer and Catherine L Tooke and John D Buynak},
  journal = {ACS infectious diseases},
  year = {2026},
  month = oct,
  doi = {10.1021/acsinfecdis.6c00607},
  url = {https://europepmc.org/article/MED/42917105},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - JDB-1-200, an Atypically Modified Carbapenem with Standalone In Vitro Activity against KPC-Producing Enterobacterales.
AU  - Taariq Hassan
AU  - Svanik Jaikumar
AU  - Diya Patel
AU  - Pojun Quan
AU  - Maidileyvis Castro Cabello
AU  - Jonathan E Cox
AU  - Md Mahbub Kabir Khan
AU  - James Spencer
AU  - Catherine L Tooke
AU  - John D Buynak
PY  - 2026
DA  - 2026/10/01
JO  - ACS infectious diseases
DO  - 10.1021/acsinfecdis.6c00607
UR  - https://europepmc.org/article/MED/42917105
AB  - Carbapenem-resistant Enterobacterales (CRE), including Escherichia coli and Klebsiella pneumoniae are increasingly common pathogens. Resistance in CRE is often associated with production of K. pneumoniae (KPC) carbapenemases. We report a structurally modified meropenem derivative, JDB-1-200 (i.e., 8-epi-meropenem, in which the stereochemistry of the C8 hydroxyl is inverted), displaying enhanced activity relative to meropenem against KPC-producing CRE. JDB-1-200 alone displayed superior activity (MICs of 0.5 to 1 mg/L, compared with >8 mg/L for meropenem) against several clinically relevant Enterobacterales, including KPC-producing K. pneumoniae and Citrobacter freundii. Crystallographic analysis of JDB-1-200 complexes with the E166Q deacylation-deficient KPC-2 mutant, compared with an analogous meropenem (8R-hydroxyl) complex, indicates that the improvement arises from the JDB 8S-hydroxyl group acting as a hydrogen-bond donor to the hydrolytic water, slowing acyl-enzyme hydrolysis, with similar interactions observed in a CTX-M-15:JDB-1-200 complex. Kinetic inhibition data for KPC-2 and CTX-M-15 indicate that JDB-1-200 could be used alone or alongside a β-lactamase inhibitor for effective CRE treatment.
SN  - 2373-8227
ER  -