Siderophore-Enabled Delivery of Carbapenem and Metallo-β-Lactamase Inhibitor: A Promising Strategy against Multidrug-Resistant Pseudomonas aeruginosa

Abstract

Carbapenem-resistant Pseudomonas aeruginosa (CRPA), a World Health Organization high-priority pathogen, represents a major clinical threat due to limited treatment options. Its intrinsic resistance is driven in part by extremely low outer-membrane permeability, which restricts antibiotic uptake, while the increasing prevalence of metallo-β-lactamase (MBL)-producing strains, particularly NDM-expressing isolates, poses a critical therapeutic challenge, conferring resistance to both carbapenems and cefiderocol, with few effective inhibitors available. In this study, we evaluated the potential of a series of unique biomimetic siderophore conjugates in combating CRPA. As an initial approach, tris-catecholate siderophore–meropenem conjugates were synthesized and demonstrated to overcome nonenzymatic carbapenem resistance in P. aeruginosa, including porin loss and efflux upregulation, in an iron-dependent manner. We then targeted MBL-expressing CRPA by vectorizing a recently developed broad-spectrum MBL inhibitor, indole carboxylates (InC), which is largely ineffective against P. aeruginosa, likely due to poor permeability. These conjugates restored inhibitor activity and effectively reversed meropenem and cefiderocol resistance in MBL-producing clinical isolates, both in vitro and in a Galleria mellonella infection model. Together, these findings highlight the design and potential of siderophore conjugates as a versatile platform to revive the efficacy of life-saving antibiotics against multidrug-resistant Gram-negative pathogens.