A chloride-responsive molecular switch: driving ion transport and empowering antibacterial properties.

A molecular switch was developed to recognize and transport Cl- across lipid bilayers. The XRD-crystal structure and NOESY NMR spectra of a potent 4-aminoquinazoline analogue confirmed Cl--induced conformation changes. Systematic biophysical studies revealed that the quinazoline moiety forms cooperative interactions of H+ and Cl- ions with the thiourea moiety, resulting in the transport of H+/Cl- across the membranes. A pH-dependent analysis revealed that the transport of Cl- by the potent compound increased in an acidic environment. The potent compound could also transport H+/Cl- across Gram-positive bacteria, leading to antibacterial activities.

Stimuli-responsive release of active anionophore from RGD-peptide-linked proanionophore.

Integrin-mediated cellular delivery was attempted to optimize practical applications of hydrophobic ionophores. The potent ionophore preferentially transports H+/Cl- across the lipid bilayers following a symport mechanism. The RGD-peptide-appended tag was stimulated by glutathione to generate the active ionophore, prompting the transport of Cl- under the cellular environment.

Quinoline Thiourea-Based Zinc Ionophores with Antibacterial Activity.

The increasing resistance of bacteria to commercially available antibiotics threatens patient safety in healthcare settings. Perturbation of ion homeostasis has emerged as a potential therapeutic strategy to fight against antibacterial resistance and other channelopathies. This study reports the development of 8-aminoquinoline (QN) derivatives and their transmembrane Zn2+ transport activities. Our findings showed that a potent QN-based Zn2+ transporter exhibits promising antibacterial properties against Gram-positive bacteria with reduced hemolytic activity and cytotoxicity to mammalian cells. Furthermore, this combination showed excellent in vivo efficacy against Staphylococcus aureus. Interestingly, this combination prevented bacterial resistance and restored susceptibility of gentamicin and methicillin-resistant S. aureus to commercially available ß-lactam and other antibiotics that had lost their activity against the drug-resistant bacterial strain. Our findings suggest that the transmembrane transport of Zn2+ by QN derivatives could be a promising strategy to combat bacterial infections and restore the activity of other antibiotics.

Transmembrane fluoride anion transport by meso-3,5-bis(trifluoromethyl)phenyl picket calix[4]pyrrole.

Meso-3,5-bis(trifluoromethyl)phenyl picket calix[4]pyrrole 1 displays excellent fluoride anion transport activity across artificial lipid bilayers showing EC50 = 2.15 µM (at 450 s in EYPC vesicle) with high fluoride over chloride ion selectivity. The high fluoride selectivity of 1 was ascribed to the formation of a sandwich type π-anion-π interaction complex.