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

Project Code: MRC24IIAREx Ballou

Research Theme: Infection, Immunity, Antimicrobial Resistance and Repair

Project Code

MRC24IIAREx Ballou

Research Theme

Infection, Immunity, Antimicrobial Resistance and Repair

Project Summary Download

MRC24IIAREx-Ballou-iCase

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 dwelling 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 to mitigating fungal infections.

Description

Human fungal pathogens are an underestimated threat to human health, and those caused by soil dwelling Mucorales fungi are among the most poorly understood yet most dangerous. Infections result from inhalation of spores from the environment or via catastrophic wounds such as those experienced by blast trauma victims1. Mucorales fungi are highly resistant to most currently available antifungal drugs, so require innovative approaches for new patient therapies.

The importance of one aspect of Mucorales infections has only recently been appreciated: infections are frequently polymicrobial. Approximately 40% of clinical Mucorales isolates host endohyphal bacteria that can be either transiently associated or form obligate “holobionts”. We previously showed that these pairing can have unanticipated impacts, increasing fungal stress resistance and pathogenesis2. This project builds on this observation to identify signaling factors generated during bacterial-fungal interactions. Specifically, this project will identify inhibitors of Mucorales-bacterial interactions underpinning virulence, and fill a major gap in knowledge around biologically relevant secreted products. As part of this project, you
will:

  1. Perform high-through-put (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, then prioritize and characterise hits and their modes of action.
  3. Build understanding of how secreted factors influence fungal and bacterial behaviors.

This project will take place at the MRC Centre for Medical Mycology, where you will be co-supervised by Dr Ballou, PhD, and Dr Corzo-Leon, MD PhD, experts in Mucorales-bacterial interactions. You will gain proficiency in performing high-throughput drug and phenotypic screens, as well as training in data handling and analysis, hypothesis generation, and hypothesis testing. Dr Ballou places a strong emphasis on student-led research, encouraging each member of the team to identify and follow promising research trajectories.

You will also benefit from a 3 month placement with the Dstl partner labs, enabling further training and exposure to alternate modes of working. Within the Centre for Medical Mycology, you will be part of a larger cohort of PhD students and postdocs and will benefit from interaction with a vibrant community of post-doctoral and senior scientists, including ample opportunity to present your work both at local meetings and international conferences. You will also be encouraged to participate in outreach events as part of the CMM’s strong commitment to public engagement.

References

  1. Rodriguez CJ, Ganesan A, Shaikh F, Carson ML, Bradley W, Warkentien TE, Tribble DR. 2022. Combat-Related Invasive Fungal Wound Infections, Military Medicine, 187(2) 34–41,
  2. Itabangi H, Sephton-Clark PCS, Tamayo DT, Zhou X, Starling GP, Mahamoud Z, Insua I, Probert M, Correia J, Moynihan PJ, Gebremariam T, Gu Y, Ibrahim AS, Brown GD, King JS, Ballou ER, Voelz K. 2022. A bacterial endosymbiont of the fungus Rhizopus microsporus drives phagocyte evasion and opportunistic virulence. Current Bilogy 32(5):1115-1130.e6.
  3. Tansarli GS, Eschbacher J, Schroeder LK, SenGupta D, Lieberman JA. 2023 Mycetohabitans rhizoxinica in Patients with Rhinocerebral Mucormycosis Due to Rhizopus microsporus. Mycopathologia.

Lead Supervisor

Dr Elizabeth Ballou

Lead Supervisor Email

E.Ballou@exeter.ac.uk

University Affiliation

Exeter