Terramide A: a novel ironophore targeting Acinetobacter baumannii with mechanistic insights into bacterial iron deprivation

Acetobacter baumannii poses escalating clinical challenges due to its exceptional adaptability, demanding innovative antimicrobial strategies. This study pioneers an investigation into the antibacterial efficacy and molecular mechanism of Terramide A, a hydroxamate siderophore isolated from Aspergillus terreus, against notorious A. baumannii . Employing a multidisciplinary approach integrating phenotypic characterization with mechanistic interrogation, we demonstrate that Terramide A exerts significant inhibitory effects against A. baumannii and P. aeruginosa , pathogens critically dependent on siderophore-mediated iron acquisition for survival and virulence. Structural characterization underlines the hydroxamate moieties of Terramide A presumably supports its hypothesized role as a fungal siderophore, involving competitive iron sequestration and bacterial homeostasis. Subsequently, multi-omics investigation of susceptible strain AB19606 delineated a metabolic collapse cascade due to iron acquisition competition: (1) impairment of central metabolism and energy production through oxidative phosphorylation (OXPHO) inhibitions; (2) compromised stress adaptation and bacterial flexibility; (3) compensatory overactivation of siderophores biosynthesis and transportation, depleting metabolic intermediates and exacerbating stress; (4) coordinated suppression of virulence determinants, such as secretory systems and biofilm formation. These molecular derangements translated into phenotypic deficits, including quorum sensing, diminished autoinducer peptides production, and morphological/functional abnormalities. In vivo evaluation in a rat skin wound infection model further demonstrated that Terramide A promotes wound healing and mitigates inflammation, supporting its antibacterial efficacy. These findings establish Terramide A as a promising antibacterial agent and provide critical insights into iron-competitive antimicrobial strategies to exploit micro-nutrient deprivation and metabolic dysfunction. However, further research is needed to optimize the siderophore-based scaffold, clarify its mechanisms, and assess therapeutic potential.