Exploring polyamine toxicity and resistance in epidemic bacterial skin pathogens

Abstract. Methicillin Resistant Staphylococcus aureus (MRSA) is an important human pathogen that exerts a tremendous negative impact on human health. S. aureus stands out among other species of Coagulase-Negative Staphylococci (CoNS) in that S. aureus specifically has evolved high pathogenic potential. Streptococcus pyogenes (Group A Streptococcus or GAS) is also a dangerous human pathogen, and both species primarily inhabit human skin. Polyamines or positively charged aliphatic molecules produced by almost all living things. Curiously, both MRSA and GAS lack polyamines and certain ones are highly toxic to both pathogens. The high level of polyamines in human skin must exert a tremendous selection on these pathogens because epidemic clones of both have evolved resistance to polyamines. This proposal seeks to understand how polyamines enter the cell, how they kill these bacteria and how these epidemic clones evolved resistance. We will also explore developing novel synthetic polyamines that are capable of killing even resistant clones. We will validate that their mechanism of action is the same as natural polyamines. This might lead to the development of novel effective topical therapeutics against two important human pathogens.