Lasso Peptide-Based Biocontrol Agents for Selective Inhibition of Harmful Cyanobacterial Blooms

Background

Cyanobacterial harmful algal blooms (HABs) are a growing concern in freshwater environments worldwide, driven by nutrient pollution and climate change. These blooms, caused by the rapid proliferation of cyanobacteria, can devastate aquatic ecosystems by depleting oxygen, reducing biodiversity, and producing toxins such as microcystin and anatoxin. These toxins pose significant risks to public health, contaminating drinking water supplies and restricting recreational water use. The increasing frequency and severity of HABs, exemplified by events like the 2014 Lake Erie crisis that left half a million people without potable water, underscore the urgent need for effective and sustainable control strategies to protect both environmental and human health.

Current approaches to managing cyanobacterial blooms are limited and often problematic. Mechanical removal techniques are labor-intensive and provide only temporary relief, while chemical treatments—such as copper sulfate and other algaecides—lack specificity, frequently harming non-target aquatic organisms and disrupting ecosystem balance. These methods can also lead to the release of toxins from dying cyanobacteria, exacerbating water quality issues. Additionally, chemical residues may persist in the environment, raising concerns about long-term ecological impacts. The lack of selective, environmentally friendly solutions highlights a critical gap in current HAB management practices, necessitating the development of new technologies that can target cyanobacteria without collateral damage to freshwater ecosystems.

Technology

This technology utilizes a class of unique cyclic peptides known as lasso peptides, specifically identified and characterized for their potent and selective antimicrobial activity against cyanobacteria. These peptides, including Astexin-2, Caulonodin IV, and Benenodin-1 sulfoxide AC5, are capable of inhibiting the growth of various cyanobacterial strains—such as toxin-producing Microcystis aeruginosa and Anabaena sp.—at sub-micromolar to low micromolar concentrations. The peptides are produced recombinantly in Escherichia coli using standard molecular biology techniques and subsequently purified through chromatographic methods. Many of the most effective peptides originate from α-proteobacteria and are associated with a specific biosynthetic gene cluster subclass containing an isopeptidase gene, which appears to be a marker for anti-cyanobacterial activity. Beyond the initial set of characterized peptides, bioinformatic analysis has predicted a broader family of over a thousand related peptides with similar properties, suggesting a vast reservoir of potential biocontrol agents.

What differentiates this technology is its highly selective and environmentally friendly approach to managing harmful cyanobacterial blooms (HABs), which are a growing threat to freshwater ecosystems and public health. Unlike conventional methods that rely on mechanical removal or broad-spectrum chemical treatments—often harming non-target aquatic organisms and disrupting ecological balance—these lasso peptides specifically target cyanobacteria with minimal collateral impact. The discovery of a strong correlation between peptide potency and the presence of isopeptidase-encoding gene clusters in α-proteobacteria enables targeted identification and development of new peptides with anti-cyanobacterial activity. This selectivity, combined with the ability to produce the peptides recombinantly and the scalability potential through synthetic biology, positions the technology as a sustainable, “green” alternative for both immediate and long-term applications in aquaculture, water treatment, and large-scale freshwater management. The approach not only addresses urgent environmental challenges but also opens new avenues for precision biocontrol using naturally derived molecules.

Benefits

• Highly potent and selective antimicrobial activity against harmful cyanobacteria, including toxin-producing strains
• Environmentally friendly biocontrol method that minimizes harm to non-target aquatic organisms
• Recombinant production in Escherichia coli enables scalable peptide synthesis using standard molecular biology techniques
• Broad potential with over a thousand related peptides identified, offering a large reservoir for further development
• Novel mechanism targeting cyanobacteria through lasso peptides with unique cyclic structures and isopeptidase gene clusters
• Applicable for diverse freshwater environments such as aquaculture, ornamental ponds, and potentially large water bodies
• Offers a sustainable alternative to mechanical removal and harsh chemical treatments for managing harmful algal blooms

Applications

• Freshwater aquaculture HAB control
• Ornamental pond algae treatment
• Eco-friendly lake bloom mitigation
• Probiotic prevention of cyanoblooms

Additional info

These recombinant lasso peptides, notably Astexin-2 and Caulonodin IV, feature a unique threaded cyclic structure. Derived from $\alpha$-proteobacteria biosynthetic gene clusters containing isopeptidase genes, they exert selective antimicrobial activity against cyanobacteria, including toxin-producing *Microcystis aeruginosa*. By inhibiting growth at sub-micromolar concentrations, these purified peptides serve as high-potency biocontrol agents for freshwater harmful algal blooms, offering a selective alternative to non-specific chemical treatments.