Looking for an Achilles Heel in the deadly fungi that cause Mucormycosis at University of Exeter

Project Title: Looking for an Achilles Heel in the deadly fungi that cause Mucormycosis

Project Summary: 

Invasive infections by Mucorales fungi are life-threatening complications of severe blast trauma. Mucorales are resistant to most antifungals and cause devastating infections, yet are poorly understood. Mucorales are soil-swelling fungi and can host endosymbiotic bacteria that can influence fungal pathogenicity. We showed that removing endosymbionts can reduce fungal fitness. This project will identify compounds that target this partnership as an Achilles Heel as a strategy to mitigating fungal infections.

About the Project: 

Combat-related invasive fungal infections are life-threatening complications of severe blast trauma. They are often caused by soil-dwelling Mucorales fungi with high-level resistance to most currently available antifungal drugs. Yet devastating mucormycosis is understudied and poorly understood.

Mucorales infections can be polymicrobial: approximately 40% of clinical isolates host bacteria that can be either transiently associated or form obligate holobionts. Our unbiased survey of clinical Mucorales isolates found much more diversity than previously reported. The pairings can encompass a surprising variety of both fungal hosts and bacterial partners, spanning Mucorales genera and both gram positive and negative species.

Importantly, our data demonstrate bacteria can mediate fungal virulence by:

1. increasing fungal stress resistance, and
2. secreting factors that block host responses.

Recent clinical reports also suggest Mucorales may be infection reservoirs for bacteremia in vivo. Disrupting holobionts can reduce fungal fitness. Together, these findings suggest that compounds that disrupt holobionts may offer an important opportunity for controlling and mitigating fungal infections. Finally, our work swapping fungal host and bacterial partner reveal growth of non-host fungi can be controlled by bacterial secreted factors. This suggests such bacteria may represent an untapped source of antifungal compounds.

This project will identify inhibitors of Mucorales-bacterial interactions underpinning virulence, and fill a major gap in knowledge around biologically relevant secreted products. The student will:

1. Perform HTP screens to disrupt holobionts using panels of well-characterised chemical fragments, FDA approved and in-pipeline drugs.
2. Perform HTP screens for antimicrobial activity using a library of secreted factors generated from fungal isolates.
3. Prioritize and characterise hits and their modes of action.