Work

Metal–1,10-Phenanthroline-5,6-dione Complexes Target Multidrug-Resistant Acinetobacter baumannii: Antibacterial and Pharmacodynamic Insights

Year: 2026

Type: preprint

Abstract: The escalating threat of antimicrobial resistance underscores the need for novel therapeutic strategies against multidrug-resistant (MDR) Gram-negative pathogens. We previously demonstrated the potent antimicrobial activity of 1,10-phenanthroline-5,6-dione (phendione) complexes with silver(I) (Ag-phendione) and copper(II) (Cu-phendione) against MDR Acinetobacter baumannii . Herein, we further characterized the antibacterial activity and pharmacodynamic profiles of these complexes against six MDR clinical isolates and the reference strain ATCC19606. Exposure-response relationships, dose-fractionation regimens, post-antibiotic effects (PAEs) and the influence of bacterial inoculum on minimum inhibitory concentrations (MICs) were investigated. Potential interactions with meropenem and imipenem were assessed by checkerboard and time-kill assays, while recalcitrance was evaluated by modified disk-diffusion assays. Ag-phendione consistently exhibited bactericidal activity, whereas Cu-phendione displayed either bactericidal or bacteriostatic effects depending on the strain. Ag-phendione demonstrated greater antibacterial potency and predominantly time-dependent activity, with maximal effects observed between 6 and 12 h. Notably, dose fractionation with two administrations of 0.5×MIC at 6-h intervals maintained sustained bactericidal activity, resulting in complete eradication of all tested isolates within 24 h. MICs remained unchanged across different inoculum sizes, indicating robust activity under varying bacterial burdens. At 3.12 µg/mL, both complexes reduced bacterial populations by more than 97%. Ag-phendione produced a substantially longer PAE than Cu-phendione (1.857 versus 0.714 h). Combination assays with meropenem and imipenem predominantly showed additive interactions accompanied by significant reductions in bacterial burden. Importantly, neither complex induced detectable tolerance or heteroresistance under the conditions tested. Collectively, phendione complexes show promising antimicrobial and pharmacodynamic activity against MDR A. baumannii , warranting further investigation as therapeutic candidates.

Source: Research Square

DOI: 10.21203/rs.3.rs-10922740/v1