Appearance of a paradoxical mutant in the formidable streptococcus 🦠

Streptococcus pyogenes, or Group A Streptococcus (GAS), is a formidable pathogen responsible for over 517,000 deaths per year worldwide.


During an experimental infection by GAS, a mutant appeared in vivo that exhibited attenuated virulence. In an article published in Nature Communications, scientists explain the reasons behind the paradoxical emergence of this mutant, which affects membrane content, and the implications of this discovery for identifying new therapeutic targets.

The regulator of the fatty acid biosynthesis pathway in streptococci and its role in infection

The lipid membrane is central to all cellular transactions. Many bacteria synthesize fatty acids, precursors of lipids, essential components of membranes, via the synthesis pathway known as FASII. In the formidable pathogen Streptococcus pyogenes, or Group A Streptococcus (GAS), responsible for over 517,000 deaths per year worldwide, the expression of genes in this pathway relies on the activity of a protein called FabT, which binds to DNA and represses the expression of FASII genes.

The scientists focused on the role of FabT during GAS infection. They were intrigued by a paradox: although FabT defects are linked to attenuated virulence in animal models, spontaneous FabT mutants emerge in vivo.

The ambivalence between FabT as a repressor necessary for infection and the emergence of fabT mutants

FabT acts as a repressor of FASII, which results in the incorporation of exogenous fatty acids (eFAs) to replace their synthesis. FabT-mutated strains have lost the signal that halts the synthesis of FAs, even when eFAs are available. As a result, they produce longer FAs, leading to membrane defects. Additionally, this synthesis causes greater nutrient consumption, and consequently higher energy dissipation, without enabling bacterial growth. These two defects result in bacterial death.

Thus, the mutant fails to grow ex vivo on human tissue, or on cells or in cellular and tissue filtrates, all of which are environments where nutrients are limited. These characteristics explain the necessity of FabT during infection. Conversely, fabT mutants show a growth advantage compared to the wild-type strain when exposed to saturated eFAs, present, for example, in interstitial spaces. Indeed, saturated FAs are toxic when incorporated by the wild-type strain.

The scientists showed that the continuous activity of FASII, as seen in the fabT mutant, prevents this incorporation. Furthermore, spontaneous fabT mutants were obtained in vitro during the culture of the wild-type strain in the presence of saturated eFAs. Additionally, an ex vivo muscle model, which is rich in saturated FAs, revealed that the fabT mutant has a marked growth advantage compared to the wild-type strain. Indeed, the survival of the fabT mutant, or of wild-type GAS, depends on the bacterium's location.



These results explain the emergence of fabT mutants that improve survival in lipid-rich environments composed of saturated FAs but lead to a genetic dead end for infection.

These teams had previously demonstrated that inhibiting the FASII pathway was not a therapeutic option due to the incorporation of eFAs in vivo by various Gram-positive bacterial species. The present study indicates that, a contrario, rendering the FASII pathway constitutive by inhibiting FabT is detrimental to infection in vivo. FabT is therefore a potential therapeutic target for new therapies against specific Gram-positive pathogens, including GAS, Streptococcus agalactiae, Streptococcus pneumoniae, and Enterococcus faecalis.

Reference:
The double-edged role of FASII regulator FabT in Streptococcus pyogenes infection. Lambert C, Gaillard M, Wongdontree P, Bachmann C, Hautcoeur A, Gloux K, Guilbert T, Méhats C, Prost B, Solgadi A, Abreu S, Andrieu M, Poyart C, Gruss A* and Fouet A*.
October 4, 2024, Nature Communications, DOI: 10.1038/s41467-024-52637-3