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

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 ( ) values against all classes of β-lactamase, including imipenemase types and oxacillinase types from . Against 207 and 55 . , including carbapenemase producers, KSP-1007 at fixed concentrations of 4, 8, and 16 µg/mL dose-dependently potentiated the activity of MEM in broth microdilution MIC testing. The MIC of MEM/KSP-1007 at 8 µg/mL against was lower than those of MEM/vaborbactam, ceftazidime/avibactam, imipenem/relebactam, and colistin and similar to those of aztreonam/avibactam, cefiderocol, and tigecycline. The activity of MEM/KSP-1007 at ≥4 µg/mL against harboring metallo-β-lactamase was superior to that of cefepime/taniborbactam. MEM/KSP-1007 showed excellent activity against 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 than these comparators except for cefiderocol, tigecycline, and colistin. A 2-fold reduction in MEM MIC against 96 was observed in combination with KSP-1007. MEM/KSP-1007 demonstrated bactericidal activity against carbapenemase-producing , , and based on minimum bactericidal concentration/MIC ratios of ≤4. KSP-1007 enhanced the activity of MEM against carbapenemase-producing , , and 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.