Lipid Flippases Present a New Target for Drug Synergy
Scientists in the 3B (Biochemistry, Biophysics and Biomaterials) Lab at Seton Hall University are well aware of the growing problem of antimicrobial resistance. Drug resistant microbes present a major problem for immunocompromised patients and patients in long-term care facilities. With this in mind, Robert Tancer and Gregory Wiedman from Seton Hall, along with colleagues Chaoyang Xue, Yina Wang, and Siddhi Pawar of Rutgers University have put together a group that aims to address the issue from the direction of Drug Synergy(1). Together, these researchers have developed a new lead compound to address drug resistance in Cryptococcus neoformans.
Of the three main classes of antifungals, C. neoformans exhibits significant resistance to echinocandins. The fungus is so resistant that echinocandins are rarely used to treat fungal meningitis of C. neoformans. The joint group from Seton Hall and Rutgers have recently published a new paper entitled “Development of Antifungal Peptides against Cryptococcus neoformans; Leveraging Knowledge about the cdc50Δ Mutant Susceptibility for Lead Compound Development”(2). The cdc50Δ mutant strain of C. neoformans is more susceptible to the echinocandin drug caspofungin due to a deletion of Cdc50, the accessory protein for the P4 lipid flippase. The authors found that by creating a peptide that blocks the action of the lipid flippases the wild-type stain was also rendered susceptible to caspofungin.
The new lead compound developed by Tancer and colleagues represents an important step in developing a new class of antifungal drugs. These peptides that block fungal flippase enzymes hold the potential to work synergistically with a wide variety of existing antimicrobial drugs. This methodology may also reduce the possibility that new resistance mechanisms would arise. The joint group hopes to further study the effects of this new compound as well as developing compounds for use with other fungi. Their exciting research is presented Open Access in the journal Microbiology Spectrum.
1. Tancer RJ, Baynes K, Wiedman GR. 2021. Synergy among humimycins against methicillin-resistant Staphylococcus aureus. Pept Sci 113.
2. Tancer RJ, Wang Y, Pawar S, Xue C. 2022. Development of Antifungal Peptides against Cryptococcus neoformans; Leveraging Knowledge about the cdc50Δ Mutant Susceptibility for Lead Compound Development. Microbiol Spectr. https://journals.asm.org/doi/10.1128/spectrum.00439-22