Antibiotic-cyclodextrin-liposomes: formulation development and interaction with model bacterial membranes

Gram-negative bacteria have a strong defense against antibiotics due to the intrinsic permeability barrier of their outer membrane. Recently there has been a formulation of a new drug, PPA148, which shows good activity against all Gram-negative bacteria. This is reported antibiotic-cyclodextrin-liposome (ACL) formulation using the novel hydrophobic agent PPA148, which showed good activity against Gram-negative bacteria.

The aqueous solubility of the drug was improved by interacting with two modified betacyclodextrins: hydroxypropyl betacyclodextrin (HPBCD) and methyl betacyclodextrin (RAMEB). Although there was no significant difference in the inhibitory effect of ACL on bacteria compared to the drug/CD complex itself, it could interact with both the outer and inner membranes of the bacterial envelope, and its proposed mechanism of action was examined at the molecular level using interfacial techniques. The results suggest that liposomes act as carriers of the complex, fusing to the outer membrane and thus facilitating the release of its payload, while RAMEB can also be transported through the inner membrane. Neutron reflectivity was successfully used to demonstrate a possible envelope disruption mechanism when fluid vesicles interact with the model outer membrane.

This study demonstrates that ACLs offer great promise for hydrophobic vectors, both new drugs and those that have failed due to vectors' resistance.ACL formulations may be useful in counteracting AMR as they target OM and IM of Gram-negative bacteria while enhancing the solubility of the drug, thereby increasing its bioavailability.