People with cystic fibrosis (pwCF) frequently suffer from chronic lung infections, with being the predominant pathogen contributing to disease progression and morbidity. The increasing prevalence of multi-drug-resistant (MDR) has diminished treatment options. Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics due to their unique membrane-targeting mechanisms. OMN51, a novel bioengineered AMP derived from capitellacin, was evaluated for antimicrobial activity against in sputum samples from pwCF. This study aimed to compare the bactericidal effects of OMN51 with those of a range of conventional antibiotics known to have activity against clinical isolates derived from pwCF. clinical isolates were obtained from fifty-six unique sputum cultures of pwCF at a tertiary-university-affiliated hospital. Minimum inhibitory concentrations (MICs) of OMN51 and comparator antibiotics were determined using broth microdilution. Antimicrobial susceptibility was evaluated using the Kirby-Bauer disc diffusion method. OMN51 demonstrated in vitro bactericidal activity across all isolates, including MDR strains. MIC values for OMN51 ranged from 4 to 16 µg/mL, with no observed resistance or cross-resistance. Comparative analysis revealed the superior efficacy of OMN51 compared with conventional antibiotics. OMN51 exhibits robust in vitro activity against MDR , supporting its candidacy as a therapeutic agent for MDR associated infections. Further studies are warranted to assess pharmacokinetics and in vivo safety and efficacy. OMN51 represents a first-in-class, membrane-targeting therapeutic showing promise against MDR .