Cocktails and low concentrations; effects of antimicrobial peptide combinations on bacterial resistance

• Applicant: Ronan Murphy, Ph.D.
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Microbial Ecology and Applied Microbiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534311948

The decreased and decreasing efficacy of antibiotics against bacterial infections due to the antimicrobial resistance crisis requires urgent action and solutions. A major avenue of exploration in the search for new antimicrobial strategies is the use of antimicrobial peptides (AMPs); naturally occurring innate defence peptides found across all kingdoms of life. AMPs have been proposed as and are currently being investigated as both direct acting agents and antibiotic adjuvants. This includes in the treatment of Staphylococcus aureus infections, one of the most serious and burdensome pathogens in the world due to its versatility in infecting host sites and its ability to avoid antibiotic eradication – particularly methicillin resistant S. aureus (MRSA). While AMPs are considered to be at an advantage compared to other antibiotic classes in terms of inherited antimicrobial resistance – their activity via membrane disruption and rapid cell lysis being less likely to result in resistance development – it is less clear what the consequences of AMPs are for non-inherited antimicrobial resistance. Tolerance and persistence, the two modes of non-inherited resistance, are understudied compared with inherited resistance. Moreover, bacteria are likely to encounter host defence and administered AMPs at low, sub-inhibitory concentrations only rising to lethal levels over time, rather than at a specific and constant doses and frequently as synergistic cocktail combinations rather than alone. This project will elucidate the effects of exposure of S. aureus to AMPs in short exposures to low concentrations (priming) and AMP cocktails. Using phenotypic assaying and modelling approaches along side transcriptomic and functional analyses will shed new light on the development of non-inherited antimicrobial resistance in response to AMP cocktail priming in a manner which reflects host-pathogen interactions.

• DFG Programme: WBP Position