Revisiting oxygen toxicity: evolution and adaptation to superoxide in a SOD-deficient bacterial pathogen

Area of Science:

• Microbiology and Molecular Biology
• Evolutionary Biology
• Biochemistry

Background:

• Aerobic life relies on dioxygen (O2), but its metabolism generates toxic superoxide (O2-).
• Superoxide-scavenging enzymes (SOSEs), like superoxide dismutases (SODs), are considered essential for aerobic organisms.
• Many organisms, including pathogens, lack SOSEs, yet their survival mechanisms against superoxide remain poorly understood.

Purpose of the Study:

• To investigate the evolutionary loss of SOD in pathogenic Leptospira species.
• To identify alternative mechanisms for superoxide stress adaptation in SOSE-deficient Leptospira.
• To propose a new model for superoxide adaptation in aerobic bacteria lacking SOSEs.

Main Methods:

• Comparative genomics and phylogenetic analysis to trace SOD evolution in Leptospira.
• Heterologous expression of SOD in Leptospira to assess its functional role.
• Multi-omics approaches (transcriptomics, proteomics) to identify upregulated factors under superoxide stress.
• Metabolic pathway analysis focusing on leucine and cysteine biosynthesis.

Main Results:

• SOD was ancestral in Leptospira but lost in pathogenic species; its reintroduction did not enhance superoxide tolerance.
• Leptospira interrogans adapted to superoxide through inheritable upregulation of a genetic locus including an MFS transporter.
• Superoxide stress significantly upregulated isopropylmalate synthase (LeuA2) and the cysteine biosynthesis pathway, indicating metabolic rewiring.

Conclusions:

• Pathogenic Leptospira have evolved alternative strategies to combat superoxide toxicity in the absence of SODs.
• Redox-based metabolic reprogramming, particularly involving sulfur metabolism and leucine biosynthesis, is key to superoxide adaptation.
• This study challenges the universal requirement for SOSEs and proposes a novel model for aerobic survival in SOSE-deficient bacteria.