The antimicrobial peptide kills bacteria by binding to a protein target called DnaK. DnaK is a special type of protein called a heat-shock protein, responsible for correcting misshapen proteins. When the antimicrobial peptide binds to DnaK, it prevents DnaK from doing its protein-repair work, killing the bacteria.The Wistar research team studied the binding of engineered analogs of pyrrhocoricin to a series of bacterial strains. As they anticipated based on their previous investigations, they found a complete correlation between the peptide binding to a small fragment of bacterial DnaK and bacteria killing. The researchers also confirmed that the peptide does not bind to the mouse or human protein equivalents to DnaK, further suggesting that the peptide would not be toxic to mammals.
The investigators identified a possible binding surface for the antimicrobial peptide on an E. coli DnaK fragment. Knowledge of this binding site could lead to the development of new drugs tailored to combat E. coli. It may also be possible to develop drugs that would kill bacteria that are unresponsive to native pyrrhocoricin, but for which the DnaK structure is known.
In related ongoing studies, Otvos and his team have shown that analogs of pyrrhocoricin are able to kill clinical strains of resistant bacteria that cause urinary, gastrointestinal and respiratory-tract infections. In a mouse H. influenzae lung infection model, the researchers have shown that a pyrrhocoricin analog can dramatically reduce bacterial counts in the lungs and be administered in a non-invasive way. These studies are demonstrating that engineered antibacterial peptides can be used in a clinical setting against bacteria with resistance to existing antibiotics.