Multifaceted roles of carboxyl compounds in antibiofilm potency and resistance modulation in <i>Acinetobacter baumannii</i>

The escalating threat of multidrug-resistant (MDR) <i>Acinetobacter baumannii</i> is primarily driven by its robust biofilm-forming capacity and complex antimicrobial resistance mechanisms. This review comprehensively explores the pivotal role of the carboxyl functional group in modulating biofilm-associated virulence, quorum sensing (QS), and resistance pathways in <i>A. baumannii</i>. We emphasize the critical regulatory functions of the BfmRS two-component system and the AbaI/R QS system in biofilm formation, antibiotic resistance, and immune evasion. A diverse range of carboxyl-functionalized compounds, including: fatty acids, terpenoids, benzoic acids, and cinnamic acids, are highlighted for their broad-spectrum antibiofilm, anti-resistance, and antimicrobial activities, achieved through mechanisms, such as: quorum quenching, efflux pump inhibition, membrane destabilization, and metal ion chelation. These compounds enhance antimicrobial efficacy and show promise as adjuvants that potentiate existing antibiotics while minimizing resistance development. Furthermore, the review discusses the carboxyl motif's role in targeting bacterial persisters, a major challenge in chronic infections, and the evolutionary constraints imposed by carboxyl-bearing compounds on resistance evolution. Despite challenges related to membrane permeability and metabolic liabilities, innovative drug design approaches and advanced delivery systems offer promising solutions. This review underscores the versatile potential of carboxyl scaffolds as multi-target therapeutic agents against MDR <i>A. baumannii</i> and other high-risk pathogens, advocating their integration into future antimicrobial and repurposing strategies.