I contributed as a co-author to a collaborative project (led by Chong Hui Koh, Quang Huy Nhat Vu, and colleagues) investigating a novel mechanism by which cationic antimicrobial polymers cross the bacterial plasma membrane.
Unlike classical cationic polymers that kill bacteria via physical membrane disruption, oligoimidazolium (OIM) carbon acids were shown to transiently deprotonate in water, forming hydrophobic N-heterocyclic carbenes (NHCs) that enable efficient membrane translocation. Only OIMs that behave as carbon acids showed potent activity — including against colistin- and multidrug-resistant bacteria — with efficacy demonstrated in murine infection models and as a prophylactic agent against bovine mastitis 1.
Follow-up work examined how the linker chemistry joining imidazolium rings in OIM chains modulates NHC persistence within a membrane-mimicking hydrophobic environment, directly affecting cytosolic uptake and antibacterial potency. A lead compound identified in this study showed superior efficacy against extended-spectrum beta-lactamase Klebsiella pneumoniae in a murine thigh infection model 2.
My role: Contributing author, supporting electrochemical/mechanistic characterization. Lead investigators: Chong Hui Koh, Quang Huy Nhat Vu, Prof Mary B. Chan-Park, and Prof Richard D. Webster (NTU).
References
2026
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Varying Carbene Persistence in Membrane as a Mechanism for Modulating Antibacterial Carbon Acid Oligomer Killing Efficacy
Quang Huy Nhat Vu, Chongyun Tan, Mallikharjuna Rao Lambu, and 7 more authors
Angewandte Chemie International Edition, May 2026
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.
2025
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Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers
Chong Hui Koh, Mallikharjuna Rao Lambu, Chongyun Tan, and 24 more authors
Nature Communications, Jul 2025
Cationic polymers have emerged as promising next-generation antimicrobial agents, albeit with inherent limitations such as low potency and limited biocompatibility. Classical cationic polymers kill bacteria via physical membrane disruption. We propose a non-classical mechanism of crossing the bacterial plasma membrane barrier, a step required for subsequent inhibition of intracellular targets, by cationic polymers which are carbon acids. Oligoimidazolium (OIM) carbon acids, instead of lysing bacteria, transiently deprotonate in water to form hydrophobic N-heterocyclic carbenes (NHCs) and exhibit efficient plasma membrane translocation. Only OIMs that are carbon acids have potent antibacterial activities against even colistin- and multidrug-resistant bacteria. OIM amide derivatives exhibit excellent antibacterial efficacy in murine sepsis and thigh infection models, while a polymeric version acts as a prophylactic agent against bovine mastitis, which is a global agricultural problem. This study unveils a promising path for the development of an alternative class of potent antimicrobial agents.