Author(s) :

Kayla Leung.

Volume/Issue :

Abstract :

Antimicrobial resistance in Acinetobacter baumannii has underscored the need for treatments beyond single-drug regimens, given high mortality rates associated with carbapenem-resistant strains. This review explores combination therapy as a framework for addressing the diverse resistance mechanisms presented by A. baumannii, including membrane modifications, efflux regulation, biofilm formation, and target-site alteration. This manuscript compares the potential integration of therapeutic pillars, including macrocyclic peptides, AI-driven drug discovery, and oxidative stress, to understand their underlying mechanisms, current applications, and translational limitations as multimodal treatment strategies. Understanding oxidative stress mechanisms is paramount for addressing persistent Antimicrobial resistance (AMR) challenges, revealing why broad Reactive oxygen species (ROS) flooding is ineffective and how localized oxidants can bypass bacterial defenses. Through case studies such as Zosurabalpin, a macrocyclic peptide with selective inhibition, and AI susceptibility models, this review highlights how an interdisciplinary approach can advance AMR therapies. Zosurabalpin’s specific mechanism of action demonstrates the value of narrow-spectrum molecules that disrupt essential structural pathways. At the same time, deep antimicrobial susceptibility phenotyping enables rapid phenotypic classification and virtual screening, significantly shortening discovery timelines. Finally, emerging compounds—including synthetic nanoparticles and antimicrobial peptides—are discussed that enhance membrane disruption and potentiate ROS-based killing. This review highlights that no single modality can overcome A. baumannii’s adaptability. Instead, the most promising and cost-effective approach is combination therapy, strategically pairing existing drugs to reduce the likelihood of resistance and improve clinical outcomes.