Detergent Conjugation Decouples Chlorpromazine Solubility from Antibacterial Activity against Bacteria Relevant for Gut Microbiota.

The water solubility of hydrophobic amine drugs is pivotal for oral bioavailability and routinely secured by hydrochloride salt formation. In the case of the antipsychotic chlorpromazine, this approach yields a cationic amphiphile with antibacterial potency, which correlates with alterations in gut microbiota. It remains to be clarified whether a covalent conjugation of chlorpromazine to a detergent, as an alternative solubilization strategy, can improve its water solubility and reduce its antibacterial potency. Here, we leverage the modular nature of an asymmetric hybrid detergent to generate a covalent chlorpromazine-detergent conjugate and evaluate its solubility and biological activity. The covalent solubilization strategy improves aqueous solubility relative to supramolecular nanocarriers and decouples drug solubility from antibacterial activity. Detergent conjugation confers solubility and membrane-permeabilizing potency, which correlates with similar cytotoxicity and reduced antibacterial potency compared to chlorpromazine hydrochloride. Collectively, our findings establish a covalent detergent solubilization strategy for hydrophobic amine drugs, provide a rationale for cytotoxicity and antibacterial activity, and highlight its potential for improving solubility and reducing potency against bacteria relevant for gut microbiota.