The inexorable increase in multidrug resistant infections combined with a decrease in new antibiotic discovery and the lack of compounds to treat recalcitrant infections, such as those associated with sepsis and chronic biofilm infections, is creating a potential crisis in human medicine. Thus it is imperative to consider alternatives to conventional antibiotics for treating infections.
Cationic host defence (antimicrobial) peptides are produced by virtually all organisms, ranging from plants and insects to humans, as a major part of their innate defences against infection. They are a key component of innate immunity and have multiple mechanisms that enable them to deal with infections and inflammation including an ability to favourably modulate the innate immune system, and distinct antibiotic and anti-biofilm activities.
We have defined a class of peptides that act against biofilms formed by multiple species of bacteria in a manner that is independent of activity vs. planktonic bacteria. We have now developed novel anti-biofilm peptides that (i) kill multiple species of bacteria in biofilms (MBEC <1 mg/ml), including the ESKAPE pathogens and other major clinically relevant Gram negative and Gram positive bacteria, including, (ii) work synergistically with antibiotics in multiple species and in animal model infections, and (iii) are effective in human skin organoid and animal models of biofilm and abscess infections. Structure activity relationships studies showed no major overlap between anti-biofilm and antimicrobial (vs. planktonic bacteria) activities, and indeed organisms completely resistant to antibiotic peptides can still be treated with anti-biofilm peptides. The action of such peptides is dependent on their ability to trigger the degradation of the nucleotide stress signal ppGpp.