Resistance to antimicrobial peptides: rates and mechanisms (360G-Wellcome-211791_Z_18_Z)

Peptides, as a class of antimicrobials, raise particular challenges and opportunities around antimicrobial resistance. The opportunity of antimicrobial peptides (AMPs) is the breadth of the class, with different modes of action among many, readily synthesised, sequences. Spontaneous resistance rates vary among antimicrobials. Thus, while ‘evolution-proof antimicrobials’ is over-blown, there is real opportunity to identify AMPs with lowered resistance rates. But the vastness of sequence space is also a challenge – possible peptides just 10 residues long are as numerous as cells in the human body. Another challenge is the innate immune system’s use of AMPs – AMPs might, clinically, make human-associated microbes dangerously cross-resistant to human AMPs. This project will address both challenges and opportunities. Focusing on Staphylococcus aureus, the first goal will be to measure resistance rates across a systematic library of AMPs. Such assays will reveal sequence effects on resistance rates, without testing an impossibly large universe of AMPs. The second and third goals will use the set of resistant strains generated by the first goal to understand the processes of AMP resistance and cross-resistance, both at the phenotypic and genetic levels. Together, these offer a new route into rational design of novel antimicrobials with minimised resistance rates.