Formulation strategies can play an important role in enhancing antimicrobial treatment regimens. 1) Dermal formulations for Candida auris skin infections: Bolalipids are amphiphilic molecules with two polar headgroups connected by one or two hydrophobic alkyl chains. They were originally isolated from membranes of thermoacidophilic Archaea and possess various pharmaceutical / medical uses, including antimicrobial activity (Hughes, 2021). We have shown that synthetic bolalipids are excellent solubilizing agents for poorly soluble drugs but are cytotoxic in cell culture (Li, 2022). In contrast, they are well-tolerated on the skin (pilot data). We hypothesize that dermal bolalipid formulations of antifungal agents can enhance topical activity of drugs against Candida auris skin infections. 2) Liposomal formulations with improved antibiotic penetration across Gram-negative bacterial membranes: A different formulation approach is required for effective P. aeruginosa therapies. It is well-known that the intrinsic permeability barrier Gram-negative pathogens reduces therapeutic efficacy. Our associate, R. Harvey, developed an antibiotic-in-cyclodextrin-in-liposomes formulation which targets both the bacterial outer and inner membranes, demonstrating enhanced permeation across E. coli membranes (Vandera, 2020). We hypothesize that this formulation strategy can be applied to enhance drug penetration in P. aeruginosa.

The antimicrobial activity (minimum inhibitory concentration; MIC) of standard-of-care (SoC) compounds for C. auris and P. aeruginosa will be assessed as neat drug solutions and as formulations. The antimicrobial activity of formulations alone will also be assessed. Novel compounds identified by AIDD project partners (see participating faculty list) will also be formulated to assess synergistic effects between drug and formulation. Formulation of compound combinations (polypharmacy) will be assessed for synergistic activity. In parallel, cytotoxicity of the formulations will be evaluated, and drug permeation studies conducted.