In vitro activities of zosurabalpin and comparator antimicrobials against clinical isolates of carbapenem-resistant Acinetobacter baumannii

ABSTRACT Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a major therapeutic challenge due to the limited availability of effective treatment options and is associated with substantially increased mortality in healthcare-associated infections. Zosurabalpin (ZAB, RG6006) is a novel macrocyclic peptide (MCP) antibiotic that exerts its antibacterial activity by inhibiting lipopolysaccharide transport, ultimately leading to bacterial cell death. This study evaluated the in vitro activities of ZAB and other antimicrobial agents against clinical CRAB isolates. A total of 206 clinical A. baumannii isolates were collected, including 189 CRAB and 17 carbapenem-susceptible A. baumannii (CSAB). Minimum inhibitory concentrations (MICs) of ZAB were determined using broth microdilution in cation-adjusted Mueller–Hinton broth supplemented with 20% heat-inactivated horse serum. MICs of 11 other comparator agents, including cefiderocol (FDC) and colistin (COL), were determined following Clinical and Laboratory Standards Institute (CLSI) guidelines. A. baumannii NCTC 13304 was used as the quality control strain for zosurabalpin. MIC values for A. baumannii NCTC 13304 tested with ZAB ranged from 0.03 to 0.06 µg/mL (reference range: 0.016–0.12 µg/mL). ZAB demonstrated potent in vitro activity against CRAB, with MIC 50 and MIC 90 values of 0.25 and 1 μg/mL, respectively. Among FDC-resistant CRAB isolates, the MIC 50 /MIC 90 remained 0.25/1 μg/mL, and for COL-resistant CRAB isolates, the MIC 50 /MIC 90 was 0.5/2 μg/mL. Notably, a CRAB isolate, which was resistant to both FDC and COL, exhibited a ZAB MIC of 0.5 μg/mL. This study demonstrated that ZAB exhibited potent in vitro activity against CRAB, independent of resistance to FDC and/or COL. These findings support ZAB as a promising therapeutic candidate for difficult-to-treat CRAB infections. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii (CRAB) remains a major challenge in clinical practice because of limited treatment options. Zosurabalpin (ZAB) is a first-in-class macrocyclic peptide antibiotic that has been proposed as a potential therapeutic agent for CRAB infections; however, data on its in vitro activity against clinical isolates remain limited. This study provides comprehensive in vitro susceptibility data for ZAB against clinical CRAB isolates, including strains resistant to colistin and cefiderocol. Our findings demonstrate that ZAB retains in vitro activity against CRAB, including isolates resistant to colistin and/or cefiderocol, and support its potential as a promising therapeutic option for the treatment of difficult-to-treat CRAB infections.