Targeted fungal antibody–drug conjugates for candidalysin neutralisation in Candida albicans infection

About the project

About the Project Fungal infections are an increasing global health problem, and treatment options remain limited. This PhD project will develop a new therapeutic strategy for Candida albicans , a major human fungal pathogen. Rather than simply trying to kill fungal cells, the project will target candidalysin, a peptide toxin produced by invasive hyphae of C. albicans that damages epithelial tissues and drives inflammatory signalling during infection. The project will test the concept that candidalysin can be neutralised using targeted fungal antibody–drug conjugates. In this approach, a fungal-binding antibody would localise an inhibitory payload to the fungal–host interface, where candidalysin causes tissue damage. This offers a new anti-virulence principle for fungal infection: protecting host tissue from toxin-mediated injury while complementing existing antifungal approaches. The student will work at the interface of fungal pathogenesis, epithelial biology, peptide chemistry, antibody therapeutics and industrial biotechnology. The project starts from preliminary candidalysin-inhibitory peptides identified by the academic team. These provide a strong foundation for developing payloads that can be optimised, modified and potentially conjugated to fungal monoclonal antibodies. The first phase of the project will characterise existing candidalysin-inhibitory peptides. The student will test their ability to block candidalysin-mediated epithelial damage using established Candida infection and epithelial cell assays. Readouts may include epithelial cytotoxicity, calcium influx, inflammatory signalling, cytokine production, peptide stability and host-cell safety. These studies will identify which peptides have the best potency, selectivity and suitability for further development. The second phase will optimise candidate payloads. Peptide analogues will be designed to improve stability, solubility, activity and tolerance of linker attachment. Approaches may include truncation, residue substitution, terminal modification, cyclisation, incorporation of non-natural amino acids, modelling, pharmacophore analysis and focused synthesis. The project will also explore whether peptidomimetic or small molecule candidalysin inhibitors can provide more developable alternative payloads. The third phase will investigate antibody-mediated targeting in collaboration with Brigid Bio, an SME developing antibody-based therapeutics for serious fungal infections. Selected payloads will be assessed for compatibility with fungal monoclonal antibodies, and candidate conjugates will be characterised for purity, antibody binding, aggregation, stability, payload release and biological activity. Appropriate controls will include free payload, unconjugated antibody, antibody plus free payload and linker-payload comparators. In the final phase, the student will integrate biological and chemical data to define the most promising targeted candidalysin-neutralisation strategy. Lead candidates will be tested in purified candidalysin assays, epithelial cell models and live C. albicans infection models, with further ex vivo or in vivo proof-of-concept studies considered where appropriate and subject to approvals. Key endpoints will include reduction of epithelial damage, inflammatory signalling, fungal burden where relevant, and tolerability. The student will receive interdisciplinary training across academic and industrial environments. At King’s College London, they will gain expertise in C. albicans pathogenesis, candidalysin biology, mammalian epithelial cell culture, fungal infection assays, peptide and peptidomimetic design, chemical biology and analytical characterisation. Through Brigid Bio, they will gain experience in fungal antibody platforms, antibody binding assays, ADC developability, intellectual property, translational decision-making and industrial project development. This PhD is suited to an applicant interested in innovative antifungal therapeutics and willing to work across disciplines. The successful student will develop rare skills spanning fungal biology, chemical biology and antibody-based therapeutic development, while contributing to a first-in-class strategy to neutralise a major fungal virulence factor.

Research areas