In vitro activity of zosurabalpin against a global set of carbapenem-resistant-A. baumannii clinical isolates.

Abstract

The limited treatment options for carbapenem-resistant Acinetobacter baumannii (CRAB)-invasive infections highlight the urgent need for novel therapeutic agents. Zosurabalpin is a first-in-class tethered macrocyclic-peptide targeting the LptB₂FGC-complex. In this study, we evaluated the in vitro activity of zosurabalpin a1gainst a diverse global set of CRAB clinical isolates. We compared zosurabalpin's activity with currently available antibiotics, including colistin, cefiderocol, sulbactam-durlobactam, as well as rifabutin. Additionally, we assessed different AST methods to support reliable zosurabalpin susceptibility testing. We included a total of 304 CRAB clinical isolates from Switzerland, Israel, Turkey, Ethiopia, Pakistan, and Australia. Among them, 297 carried plasmid-borne-carbapenemases (236 OXA-type-producers, 60 NDM-type-producers alone or in combination with OXA-type-carbapenemases, and 1 GES-14-producer), 3 were GES-ESBL-producers, and 4 isolates were without acquired ESBL/carbapenemases. We determined zosurabalpin minimal inhibitory concentrations (MICs) by broth microdilution using cation-adjusted Mueller-Hinton broth (CA-MHB) supplemented with 20% heat-inactivated horse serum, in accordance with CLSI recommendations, as well as using plain CA-MHB, with reading at substantial reduction (80% growth inhibition). We determined MICs of the remaining antibiotics according to EUCAST methods: colistin and sulbactam-durlobactam (with fixed durlobactam concentration of 4 mg/L) with CA-MHB, cefiderocol with iron-depleted CA-MHB, and rifabutin with RPMI. The zosurabalpin MIC distribution using the CLSI-based method ranged from ≤0.032 to 2 mg/L (MIC₉₀ = 0.5 mg/L), with no CRAB isolates showing MICs displaying MICs suggestive of high-level acquired resistance. A single isolate with MIC = 2 mg/L harbored a 13-amino-acid deletion in lptD (position 692), potentially affecting outer-membrane LPS biogenesis. MIC₉₀ values for cefiderocol, sulbactam-durlobactam, colistin, and rifabutin were 8, 16, 1, and 2 mg/L, respectively. Zosurabalpin showed no cross-resistance with any of the tested antimicrobials. Zosurabalpin MICs in CRAB isolates were generally low, including metallo-β-lactamase-producing-CRAB. The low MICs show a high potential to overcome current treatment limitations; however, mutations in lptD may contribute to resistance emergence and should be further studied.