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

Koji Takemoto; Ryo Nakayama; Koichi Fujimoto; Yumiko Suzuki; Yukiko Takarabe; Masako Honsho; Sachiko Kitahara; Yoshihiko Noguchi; Hidehito Matsui; Tomoyasu Hirose; Yukihiro Asami; Jun Hidaka; Toshiaki Sunazuka; Hideaki Hanaki

doi:10.1128/aac.01602-23

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 May 6:e0160223. doi: 10.1128/aac.01602-23. Online ahead of print.

Authors

Koji Takemoto¹, Ryo Nakayama¹, Koichi Fujimoto¹, Yumiko Suzuki^{2

3}, Yukiko Takarabe², Masako Honsho^{2

3}, Sachiko Kitahara¹, Yoshihiko Noguchi^{2

3}, Hidehito Matsui^{2

3}, Tomoyasu Hirose^{2

3}, Yukihiro Asami^{2

3}, Jun Hidaka¹, 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 (K_i _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.