Synthetic aminoglycoside derivatives as anti-virulence agents against multidrug-resistant Acinetobacter baumannii

Abstract

Acinetobacter baumannii presents a severe clinical challenge in critical care due to its rapid acquisition of drug resistance and its ability to form dense biofilms on medical equipment. While traditional antibiotic research focuses almost exclusively on essential bacterial viability targets, targeting virulence factors at sub-inhibitory concentrations (sub-MIC) offers an alternative approach to reduce pathogen persistence without driving immediate resistance. This systematic review synthesizes the literature published between January 2010 and July 2026 that evaluates chemically modified aminoglycoside derivatives designed to bypass aminoglycoside-modifying enzymes (AMEs) and impair A. baumannii virulence pathways. Evidence from the included studies indicates that targeted modifications to the 2-deoxystreptamine core, specifically inserting hydrophobic or amphiphilic side chains, restore susceptibility in carbapenem-resistant A. baumannii (CRAB) strains. Furthermore, these derivatives significantly reduce biofilm biomass (often by over 80% at 21×MIC) and restrict surface twitching motility. Computational docking models across these studies point to multi-target engagement, where modified derivatives interact directly with outer membrane protein A (OmpA), the quorum-sensing receptor AbaR, and the response regulator BfmR. Rational scaffold engineering of aminoglycosides offers a viable approach to develop dual-action agents that combine direct antibacterial activity with phenotypic disarming.