Varying Carbene Persistence in Membrane as a Mechanism for Modulating Antibacterial Carbon Acid Oligomer Killing Efficacy

Abstract

ABSTRACT We previously proposed that cationic oligoimidazolium (OIM) carbon acids kill bacteria via an N‐heterocyclic carbene (NHC)‐assisted translocation process to reach intracellular targets. Herein, we found that the linkers joining the imidazolium rings in OIM chains profoundly affect the oligomers’ cytosolic uptakes, which correlate with their antibacterial potency. In a hydrophobic environment (DMSO) mimicking a bacterial membrane bilayer, different OIM NHCs were found to be non‐transient, and persistent, but with measured half‐lives varying from 15.6 to 75.9 min, depending on the linkers and indicating that increased linker‐NHC interaction stabilizes the NHC and leads to increased NHC lifetimes. NHC is more hydrophobic than the precursor imidazolium charge, so that linker‐stabilized NHCs with longer lifetimes result in increased observed OIM net hydrophobicity measured via LC‐MS retention time. More hydrophobic OIM copolymers persist in membranes rather than translocate to the cytosol, and vice versa. A lead compound (15) shows superior efficacy against extended‐spectrum beta‐lactamase Klebsiella pneumoniae in a murine thigh infection model. This study establishes linker‐stabilized NHC in the membrane as a key handle to tune the antibacterial efficacy of cationic carbon acids, providing insights for rational design of next‐generation cationic antimicrobials to tackle multi‐drug‐resistant bacteria.