Structure–activity relationships of canonical and methyl-substituted isoprenoids delineate determinants of antimetabolic activity in Pseudomonas aeruginosa

Canonical and non-canonical isoprenoids offer structurally diverse scaffolds for examining how carbon chain length, methyl-substitution pattern, molecular skeleton, and functional group chemistry influence bacterial metabolic activity. In this study, canonical C5/C10 terpenes and novel non-canonical, methyl-substituted C6/C7/C11 isoprenoids were systematically evaluated against the clinical isolate Pseudomonas aeruginosa ESP050. The comparative analysis showed that antimetabolic activity was not governed by carbon number alone. Short-chain non-canonical C6-C7 isoprenoids displayed comparatively stronger and more discriminating suppression profiles, than C10-C11 compounds exhibited greater compound-specific heterogeneity. Among C7 dimethyl-isoprenol isomers, the position of the methyl substitution significantly influenced activity threshold, recovery dynamics and sustained suppression, indicating that positional isomerism is a key determinant of the antimetabolic phenotype. In the C10 class, the oxygenated linear compound geraniol demonstrated a more prolonged tendency for metabolic suppression compared to the hydrocarbon bicyclic monoterpenes 3-carene and β-pinene. Furthermore, C11 derivatives demonstrated that methylation modulates activity in a scaffold- and position- dependent manner rather than uniformly enhancing efficacy. Overall, these findings indicated that isoprenoid antimetabolic activity arises from the combined effects of chain length, methyl substitution position, molecular skeleton and oxygenation state, supporting the prioritization of selected C6-C7 scaffolds for further antimicrobial evaluation against P. aeruginosa.