In vitro and in vivo activities of KSP-1007, a broad-spectrum inhibitor of serine- and metallo-β-lactamases, in combination with meropenem against carbapenem-resistant Gram-negative bacteria

  • Antimicrob Agents Chemother. 2024 Jun 5;68(6):e0160223. doi: 10.1128/aac.01602-23.
Koji Takemoto  1 ,  Ryo Nakayama  1 ,  Koichi Fujimoto  1 ,  Yumiko Suzuki  2  3 ,  Yukiko Takarabe  2 ,  Masako Honsho  2  3 ,  Sachiko Kitahara  1 ,  Yoshihiko Noguchi  2  3 ,  Hidehito Matsui  2  3 ,  Tomoyasu Hirose  2  3 ,  Yukihiro Asami  2  3 ,  Jun Hidaka  1 ,  Toshiaki Sunazuka  2  3 ,  Hideaki Hanaki  2  3
Affiliations
  • 1. Drug Research Division, Sumitomo Pharma Co., Ltd., Osaka, Japan.
  • 2. Ōmura Satoshi Memorial Institute, Kitasato University, Tokyo, Japan.
  • 3. Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
PMID: 38709005 DOI: 10.1128/aac.01602-23
Abstract

KSP-1007 is a novel bicyclic boronate-based broad-spectrum β-lactamase inhibitor and is being developed in combination with meropenem (MEM) for the treatment of infections caused by carbapenem-resistant Gram-negative bacteria, a global health concern, and here, we describe its characteristics. KSP-1007 exhibited low apparent inhibition constant (Ki app) values against all classes of β-lactamase, including imipenemase types and oxacillinase types from Acinetobacter baumannii. Against 207 Enterobacterales and 55 A. baumannii, including carbapenemase producers, KSP-1007 at fixed concentrations of 4, 8, and 16 µg/mL dose-dependently potentiated the in vitro activity of MEM in broth microdilution MIC testing. The MIC90 of MEM/KSP-1007 at 8 µg/mL against Enterobacterales was lower than those of MEM/vaborbactam, ceftazidime/avibactam, imipenem/relebactam, and colistin and similar to those of aztreonam/avibactam, cefiderocol, and tigecycline. The in vitro activity of MEM/KSP-1007 at ≥4 µg/mL against Enterobacterales harboring Metallo-β-lactamase was superior to that of cefepime/taniborbactam. MEM/KSP-1007 showed excellent activity against Escherichia coli with PBP3 mutations and New Delhi Metallo-β-lactamase compared to aztreonam/avibactam, cefepime/taniborbactam, and cefiderocol. MEM/KSP-1007 at 8 µg/mL showed greater efficacy against A. baumannii than these comparators except for cefiderocol, tigecycline, and colistin. A 2-fold reduction in MEM MIC against 96 Pseudomonas aeruginosa was observed in combination with KSP-1007. MEM/KSP-1007 demonstrated bactericidal activity against carbapenemase-producing Enterobacterales, A. baumannii, and P. aeruginosa based on minimum bactericidal concentration/MIC ratios of ≤4. KSP-1007 enhanced the in vivo activity of MEM against carbapenemase-producing Enterobacterales, A. baumannii, and P. aeruginosa in murine systemic, complicated urinary tract, and thigh Infection models. Collectively, MEM/KSP-1007 has a good profile for treating carbapenem-resistant Gram-negative Bacterial infections.

Keywords
antibiotic resistance; beta-lactamases; carbapenems.
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