From a Hsp90 - binding protein to a peptide drug

AMMANATH AV; JANERBON A; NGUYEN, MINH-THU; WESSLING L; TRIBELLI PM; NEGA MULUGETA; BECK C; LUQMAN, ARIF; SELIM K; KALBACHER B; MACEK, BORIS; HAMMER S; JIN T; GOTZ F

microLife

Oxford Academic

Año: 2023

The Lpl proteins represent a class of lipoproteins that was first described in theopportunistic bacterial pathogen Staphylococcus aureus, where they contribute topathogenicity by enhancing F-actin levels of host epithelial cells and therebyincreasing S. aureus internalization. The model Lpl protein, Lpl1 was shown tointeract with the human heat shock proteins Hsp90α and Hsp90ß, suggesting thatthis interaction may trigger all observed activities. Here we synthesized Lpl1-derivedpeptides of different lengths and identified two overlapping peptides, namely L13 andL15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreasedF-actin levels and S. aureus internalization in epithelial cells but they also decreasedphagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor,geldanamycin, showed a similar effect. The peptides not only interacted directly withHsp90α, but also with the mother protein Lpl1. While L15 and L13 significantlydecreased lethality of S. aureus bacteremia in an insect model, geldanamycin didnot. In a mouse bacteremia model L15 was found to significantly decreased weightloss and lethality. Although the molecular bases of the L15 effect is still elusive, invitro data indicate that simultaneous treatment of host immune cells with L15 or L13and S. aureus significantly increase IL-6 production. L15 and L13 represent notantibiotics but they cause a significant reduction in virulence of multidrug-resistant S.aureus strains in in vivo models. In this capacity, they can be an important drug aloneor additive with other agents.