Oral Presentation Lorne Infection and Immunity 2021

New drugs for superbugs: immunotherapeutics that enhance neutrophil clearance of Staphylococcus aureus (#31)

Jennifer A E Payne 1 , Julien Tailhades 1 , Felix Ellett 2 , Xenia Kostoulias 1 , Alex J Fulcher 3 , Daniel Irima 2 , Anton Y Peleg 1 4 , Max J Cryle 1
  1. Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
  2. BioMEMS Resource Centre, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospital for Children, and Harvard Medical School, Charlestown, MA, USA
  3. Monash Micro Imaging, Monash University, Clayton, Vic, Australia
  4. Department of Infectious Diseases, The Alfred Hospital , Melbourne, Vic, Australia

S. aureus has two superpowers: invisibility and invincibility. S. aureus has evolved a diversity of attack and counter-attack measures to our immune response, allowing it to hide and evade the innate immune defences and establish infections - almost as if it were invisible. Additionally, S. aureus readily develops resistance to antibiotics, becoming almost invincible to our treatment strategies. Methicillin-resistant S. aureus (MRSA) strains are all too common in hospital settings and cause 10,000 death a year in the USA alone. Antibiotic resistance in S. aureus is often associated with a decrease in neutrophil recruitment - a vital step in ensuring a successful immune response to the infection. In this work, we have developed improved antibiotic agents that act as dual-function agents, enhancing neutrophil recruitment and directly killing of S. aureus. Our new antibiotics exploit formylated peptides as chemoattractants for neutrophil recruitment, which is combined with the targeted binding of vancomycin to the bacterial cell wall. This attachment of a chemoattractant directly to the bacteria by vancomycin, generates a chemotactic gradient around S. aureus, guiding neutrophils to the invading S. aureus. Using the combination of in vitro assays, infection-on-a-chip and in vivo mouse models, we have determined that these antibiotic-chemoattractants improve the recruitment, engulfment and killing of S. aureus by neutrophils. This offers a new paradigm in combating antibiotic-resistant bacteria by countering the superpowers of superbugs.