Finding a peptide drug against MRSA

Over the past 30 years, infections have become difficult to treat due to the increasing prevalence of antibiotic resistance mechanisms. Of particular concern are methicillin-resistant S. aureus (MRSA) and multidrug-resistant S. aureus (MDRSA) strains that are spreading worldwide.

Multiple studies in hospitals across the United States and European Union have shown that MRSA is the most common cause of skin and soft tissue infections. MRSA colonization is associated with subsequent infection and increased morbidity and mortality.

Consequently, the economic burden from infections caused by these strains has dramatically increased in both the USA and the European Union/European Economic Area (EU/EEA). To meet this challenge, detailed research into the factors responsible for the spread and epidemiology of MRSA and MDRSA is necessary. If we better understand these factors, we can take specific measures to reduce the spread. The study “From a Hsp90 – binding protein to a peptide drug” in microLife presents a non-antibioticbased approach to reduce the pathogenicity and possibly the spread of MRSA and MDRSA.

Almost all bacteria contain bacterial lipoproteins (Lpp) on their cell surface. In Grampositive bacteria, these proteins are anchored to the cytoplasmic membrane and protrude outwards. Here, they uptake nutrients and interact with host cells.

Lpl lipoproteins belong to a class of Lpp, of which the membrane-anchored lipoprotein Lpl1 of S. aureus is a model protein. Upon infection of the host, Lpl1 binds to human Hsp90. This interaction triggers a number of responses in S. aureus such as the increased invasion of epithelial cells, increased formation of filamentous actin (F-actin) and increased virulence.

Hence, the study speculated that blocking this essential interaction could reduce the virulence of S. aureus. In an attempt to identify the Lpl1 domain that interacts with Hsp90, peptides were synthesized that derived from the Lpl1 protein. Two of these peptides, L13 and L15, indeed bound to Hsp90 and Lpl1, while the binding to the parent protein Lpl1 was rather surprising.

When epithelial cells were infected with S. aureus, adding L13 and L15 decreased bacterial invasion, F-actin formation and virulence. It was assumed that the binding of L15 and L13 to both the bacterial ligand Lpl and the host cell receptor Hsp90 prevents the activation of Hsp90.