Tailored liposomal nanotraps for the treatment of Streptococcal infections

Abstract

Background Streptococcal infections are associated with life-threatening pneumonia and sepsis. The rise in antibiotic resistance calls for novel approaches to treat bacterial diseases. Anti-virulence strategies promote a natural way of pathogen clearance by eliminating the advantage provided to bacteria by their virulence factors. In contrast to antibiotics, anti-virulence agents are less likely to exert selective evolutionary pressure, which is a prerequisite for the development of drug resistance. As part of their virulence mechanism, many bacterial pathogens secrete cytolytic exotoxins (hemolysins) that destroy the host cell by destabilizing their plasma membrane. Liposomal nanotraps, mimicking plasmalemmal structures of host cells that are specifically targeted by bacterial toxins are being developed in order to neutralize-by competitive sequestration-numerous exotoxins. Results In this study, the liposomal nanotrap technology is further developed to simultaneously neutralize the whole palette of cytolysins produced by Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis-pathogens that can cause life-threatening streptococcal toxic shock syndrome. We show that the mixture of liposomes containing high amounts of cholesterol and liposomes composed exclusively of choline-containing phospholipids is fully protective against the combined action of exotoxins secreted by these pathogens. Conclusions Unravelling the universal mechanisms that define targeting of host cells by streptococcal cytolysins paves the way for a broad-spectrum anti-toxin therapy that can be applied without a diagnostic delay for the treatment of bacterial infections including those caused by antibiotic-resistant pathogens.

Engineered Liposomes Protect Immortalized Immune Cells from Cytolysins Secreted by Group A and Group G Streptococci

“…In our previous work, we established that bacterial culture supernatants obtained from both GAS and GGS strains were highly lytic towards erythrocytes [ 21 ].…”

“…In contrast, supernatants obtained from both GGS strains were more active against Raji cells than against THP-1 cells ( Figure 1 c,d). We have previously shown that GAS strains rely to a greater extent on SLO, whereas GGS preferentially use SLS for their hemolytic activities [ 21 ]. Therefore, our data suggest that SLO and SLS differ in their ability to harm different types of immortalized immune cell lines.…”

“…SLS is a small peptide of the thiazole/oxazole-modified microcins class [ 20 ]. We showed previously that SLS binds with a low affinity to plasmalemmal phosphatidylcholine and sphingomyelin, but its exact mode-of-action is not yet fully clarified [ 21 ].…”

“…Using these interactions, it is possible to give the toxin a decoy target to divert it from attacking the host cells. We and others have developed nanotraps to capture and neutralize bacterial exotoxins, either as nanosponges composed of cell-derived lipid bilayers wrapped around a polymeric core or liposomes composed of naturally occurring purified lipids forming one or more lipid bilayers [ 21 , 28 , 29 ].…”

“…Liposomal nanotraps can neutralize exotoxins that are produced by pathogens from different families, and rely on different mode-of-action, such as CDCs, SLS, phospholipase C, or α-hemolysin [ 21 , 29 ].…”