Novel drugs against superbugs - preclinical optimizations

Repeated use of antibiotics has given rise to microbial strains that are resistant to these
therapeutic methods, making them less effective. This phenomenon - termed antimicrobial
resistance (AMR) - greatly increases the burden of a disease, both in terms of mortality
and economic impact. It is for this reason that AMR is being recognised by numerous
health associations, including the World Health Organisation, as one of the most pressing
global issues of our time. The nature of resistance is such that further use of our current
therapeutic avenues only serves to increase the prevalence of resistant strains; it is for
this reason that methods of treatment proven to be effective against these resistant strains
must be considered and investigated, making the evaluation of antimicrobial peptide
(AMP) application more critical than ever.
The term AMP refers to a diverse group of antimicrobial agents present in the innate
immune response of many living organisms. These peptides exert multiple methods of
microbicidal action, and are able to do so across a broad spectrum of pathogens, while
having high affinity and specificity for their target - this means that AMPs often display
relatively low toxicity profiles. Perhaps their most important advantage, however, is that
many drug-resistant pathogen strains remain susceptible to AMP mechanisms of action.
This feature highlights AMPs as not only a potentially more efficient therapeutic agent, but
a possible asset in the effort to combat the effects of antimicrobial resistance.
However, there are many factors to consider and account for when adapting an AMP for
therapeutic use. Additionally, a number of these factors would hinder microbicidal activity
in vivo, without becoming apparent during in vitro testing. The observed difference
between in vitro and in vivo AMP activity is undoubtedly a significant contributor to the
large discrepancy between the array of peptides listed as potential drug candidates, and
those that have undergone successful clinical trials. Therefore, in order to develop
effective application of AMP-based therapy, it is clear that these issues must be identified
and overcome.
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This project presents an opportunity to be on the forefront of development of an agent that
could impact health research on a global level. The Hilpert group is specialised in the
synthesis and modification of antimicrobial peptides. Several AMPs have been
identified that show significant antimicrobial activity against a wide spectrum of multi-drug
resistant pathogens, and so the studentship will focus on the evaluation of in vivo
performance. This is an interdisciplinary study, requiring the student to gain familiarity
with an array of molecular biology techniques (such as various forms of solid phase
peptide synthesis), as well as advanced biochemical techniques including flow cytometry
and ESI-MS. The student will also be required to develop their quantitative skills, with
regards to not only the analysis and dissemination of data, but also the familiarity with
software designed to handle large data sets gained from toxicology and efficacy studies.
Suitability of the drug will be assessed by systematically observing the interactions
between the chosen AMPs and living models of increasing biological complexity -
beginning with cell lines, before moving on to waxworms and mouse models. The peptides
will then be modified with the intention of circumventing any observed impediments to
antimicrobial function.
The challenge of antimicrobial resistance has been recognised by the MRC for some time,
as evidenced by the numerous initiatives pointed towards tackling AMR prevalence that
the Council is involved with. This studentship project aims to contribute to that same
effort, improving health prospects for those affected around the world.