Towards multiplexed in vivo phenotypic screening to improve antimicrobial drug discovery

Antimicrobial-resistant infections are prevalent worldwide, with drug-resistant strains emerging for all currently available antimicrobial drugs and the burden of disease estimated to be ~50,000 deaths/year in Europe and North America. New therapeutic targets and drugs to treat these infections are urgently needed. Unfortunately, drugdiscovery research and development (R&D) is costly in terms of time, money, and animal lives, with estimates of the cost of bringing a drug to market being $1-2.5 billion USD. Drug-discovery pipelines suffer from high failure rates, in part due to an inability to search for new drugs in vivo. The lack of knowledge of pathogen gene products essential for growth in vivo represents a significant gap in our knowledge. The ability to study host-pathogen interactions in vivo represents an exciting and scientifically important opportunity for the discovery of new biology, novel drugs and drug targets. It is a final frontier of host-interaction biology that remains inaccessible to many of the powerful high-throughput approaches shown to be successful in the past due to the experimentally intractable nature of the in vivo environment.

This project is based on an approach pioneered by our lab to harness biological evolutionary principles (natural selection, inheritance and mutation) to template the chemical evolution of novel antimicrobial drugs. This project will establish a new drug discovery approach: biology-templated synthesis (BTS), harnessing biology to guide discovery and evolution of novel antimicrobials. For BTS evolutionary principles (natural selection, inheritance and mutation) are translated into a synthetic chemistry strategy. Pathogenic microorganisms will template the chemical evolution of new antimicrobials. Initially applied to Toxoplasma for proof-of-concept, BTS will be used to discover modulators of parasite fitness and virulence within the intact murine host organism. It will enable antimicrobial screening in vivo for the first time, and the application of evolutionary principles (natural selection, mutation, inheritance) to antimicrobial discovery.

Techniques employed for the realization of this ambitious project will include CRISPR-based genome editing, small-molecule phenotypic screening, next-generation sequencing, and integrated synthetic chemical biology/chemical proteomic approaches for downstream target identification and validation campaigns. Further project details can be found at: www.nc3rs.org.uk/towards-multiplexed-vivo-phenotypic-screening-improve-antimicrobial-drug-discovery

To apply for this position, you will need to

• have a strong background in at least one of the following areas: Chemical Biology, Diversity-oriented synthesis, Molecular Cell Biology, Microbiology, Parasitology

• show commitment, enthusiasm, team working and a creative approach to problem solving.

Previous experience in molecular and cell biology techniques is preferred, but not essential.

Applicants are expected to have a First Class or Distinction Masters level degree, or equivalent, in a relevant scientific or technical discipline, such as Microbiology or Chemical Biology. Applicants must be fluent in spoken and written English. The position is fully funded, covering tuition fees, and a stipend/bursary. The position is available to students worldwide.

*How to apply*

Please send the following documents in pdf format to [Email Address Removed]
with the email subject “Application to PhD position“:

- Academic CV

- Covering letter stating the position to which you are applying to as well as why you consider yourself suitable for the post (maximum 2 pages A4)

References do not need to be included with the application, but shortlisted applicants will need to send 2 reference letters before interview.

Early applications are encouraged. Informal inquiries about this position are also encouraged and can be directed to Dr Matthew Child at [Email Address Removed]. For further information about the Child Lab applicants are encouraged to visit: www.laboratorychild.com

This position will be based at Imperial College’s South Kensington campus in central London. Applicants are advised to visit http://www.imperial.ac.uk/life-sciences/postgraduate/research/prospective-students/ for general information on becoming a PhD student in the Department of Life Sciences.