AVERT-Candida: Abafungin Versus Emerging Resistant Transmissible Candida spp.

• Applicant: Dr. Alexander Aldejohann
• Subject Area: Clinical Infectiology and Tropical Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574126562

Invasive fungal infections (IFI) pose a growing threat to global health. Among these, emerging resistant transmissible Candida species (ERTC), like Candida auris and fluconazole-resistant Candida parapsilosis, are considered major challenges for healthcare facilities worldwide. In addition to their outbreak potential and high tenacity, both pathogens are characterized by intrinsic resistances and the ability to rapidly acquire MDR phenotypes. With only 3-4 approved drug classes, new antifungal agents are urgently needed. The arylguanidine abafungin (ABF) shows antifungal in vitro activity against ERTC according to our preliminary data. ABF’s underlying mechanism, however, has not been fully identified nor confirmed. Targets associated with the cell membrane are the most promising candidates. AVERT-Candida aims to (i) further assess ABFs in vitro activity against ERTC including MDR phenotypes, record cross resistances + synergistic potentials with other antifungals, (ii) elucidate the mechanism of ABF against ERTC (iii) confirm the identified target by deletion mutants or evolved strains, which are vulnerable to cell membrane stress, lack in fitness and virulence. Broadening the in vitro activity approach, MIC-values of 40 ERTC strains (representing MDR isolates and major outbreak lines) will be determined by EUCAST broth microdilution. A subset of 10 isolates will be evaluated by checkerboard assays for synergisms (WP1). Relevant ABF targets will be addressed by a systematic analysis of all major cell membrane components and synthesis pathways. Therefore, 6 ERTC strains will be exposed to 3 different ABF concentrations, allowing ergosterol and phospholipid content measurements (by GC-MS and TLC) and thus identifying underlying target enzymes. Direct interactions between ABF and major membrane components will be checked by NMR-spectrometry. To cover possible stress-related mechanisms the transcriptome of the ABF exposed strains will be recorded by RNA-Seq. If these techniques won’t lead to target identification, strains will be repeatedly treated with subinhibitory ABF concentration selecting resistant evolved clones, which will be analysed by WGS and RNA-Seq and thus narrow down all major mechanisms beyond the cell membrane (WP2). To confirm the identified targets either ERTC deletion mutants or evolved strains, that are switched back to wild type, will be used. These will be challenged by in vitro stress assays (cell wall / cell membrane stress, osmotic stress). In addition, their virulence and resistance potentials will be assessed by the in vivo infection model G. mellonella (WP 3). AVERT-Candida aims to provide fundamental insights into the antifungal mechanism of ABF against ERTC, contributing to the development of new ERTC treatment strategies and the enhancement of the antifungal armamentarium.

• DFG Programme: Research Grants