Gram-negative bacteria possess numerous defenses against antibiotics, due to the intrinsic permeability barrier of their outer membrane, explaining the recalcitrance of some common and life-threatening infections. We report the formulation of a new drug, PPA148, which shows promising activity against all Gram-negative bacteria.
This work is the first report of an antibiotic-in-cyclodextrin-in-liposome (ACL) formulation using the novel hydrophobic antimicrobial agent PPA148, which shows promising activity against Gram-negative bacteria. The water solubility of the drug was enhanced by interaction with two modified β-cyclodextrins, HPβCD and RAMEB. Although ACL did not present significant difference in inhibition of bacteria compared to the drug/CD complex itself, it interacts with both the outer membrane and inner membrane of bacterial envelope and its proposed mechanism of action was examined at the molecular level, using interfacial techniques. Our results suggest that liposomes act as carriers of the complex, fusing into the outer membrane and thus facilitating the release of their payload, while RAMEB also enables transport through the inner membrane. Neutron reflectivity were successfully used to demonstrate the possible envelope-breaching mechanism of fluidosomes upon interaction with the model outer membrane.
The molecular understanding of ACL provided in this work demonstrate their promise as hydrophobic antimicrobial agents, either new drugs, or those that have become ineffective due to antimicrobial resistance. ACL formulations may contribute to the fight against AMR because they target both the OM and IM of Gram-negative bacteria, while enhancing the solubility of drugs and thus increasing their bioavailability.
Vandera, K-K. A., Picconi, P., Valero, M., González-Gaitano, G., Woods, A., Zain, N. M., Bruce, K., Clifton, L. A.,
Skoda, M. W. A., Rahman, K. M., Harvey, R. D., & Dreiss, C. (2020). Antibiotic-in-cyclodextrin-in-liposomes:
formulation development and interactions with model bacterial membranes. Molecular Pharmaceutics, 17(7), 2354-2369. https://doi.org/10.1021/acs.molpharmaceut.0c00096