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StAMPing out antibiotic resistance and more

Taking a lead from nature, Boston-based Lytica Therapeutics is applying cutting-edge protein engineering to create novel antimicrobial therapies that can be administered systemically to effectively kill multidrug-resistant (MDR) microorganisms. At the heart of Lytica’s therapeutic strategy are antimicrobial peptides (AMPs)—naturally occurring small proteins expressed in a range of species, from microorganisms to humans, that can kill microbial cells. The potential of AMPs as alternatives to conventional antibiotics has been recognized since their discovery more than 40 years ago, yet this potential has proved difficult to unleash in the clinic.

AMPs typically comprise 15–50 amino acids that form cationic, amphipathic peptides and predominantly act by binding to and disrupting bacterial membranes, causing the cell to lyse. This lytic effect bypasses typical resistance mechanisms and creates a higher barrier to evolutionary resistance. Despite these advantages, attempts to create new AMP antibiotics, especially those that can be delivered systemically, have met numerous challenges, including instability, poor pharmacokinetics and cytotoxicity. These hurdles have relegated development efforts to mostly topical usage focused on Gram-positive bacteria, neglecting the Gram-negative bacterial space, where antibiotic resistance can be responsible for many serious and fatal infections within the body.

Unlocking the potential of AMPs

Lytica has begun to overcome these challenges and to realize the full potential of AMPs by applying its expertise in protein engineering to the creation of novel, synthetic AMPs. Lytica’s approach employs hydrocarbon staples to create stapled AMPs (StAMPs) that enforce an α-helical structure on peptides. The α-helix created by stapling not only stabilizes cationic peptides, but also ensures they are already in the correct conformation for membrane binding.

Although this membrane-binding potential of StAMPs is a liability when nonspecific, making it bacteria-specific would turn this drawback into an advantage. And that is precisely what was achieved in research led by Rida Mourtada, who now serves as Lytica’s CSO, and Loren Walensky, a co-founder of Lytica who was recognized as one of the world’s top 20 translational researchers of 2019 by Nature Biotechnology. Through an analysis of staple-scanning and mutagenesis libraries, Mourtada and Walensky’s team identified structure–function–toxicity relationships that they used to develop a predictive algorithm for the in silico design of StAMPs that are not only stable and active but which specifically bind to Gram-negative bacterial membranes.

This work, described in Nature Biotechnology in 20191, led to an optimized lead StAMP that showed potent activity against Gram-negative bacteria, including MDR clinical isolates, but did not lyse red blood cells—a standard measure of nonspecific lytic activity—in the dose-effective range. This optimized StAMP was also well tolerated in mice, with no evidence of hemolysis or kidney damage, a toxicity issue that has plagued other AMP development efforts.

Fig. 1 | StAMPs for the treatment of pneumonia. A stapled antimicrobial peptide (StAMP) administered intravenously spares red blood cells, but, after crossing the alveolar lining, selectively binds to bacterial cells, causing lysis and cell death.

Since 2019, Lytica has continued to build on this pioneering work with funding support from the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), and the company is currently focused on developing StAMPs to treat hospital-acquired pneumonia and ventilator-associated pneumonia caused by MDR Pseudomonas aeruginosa and Acinetobacter baumannii (Fig. 1). Lytica has shown that StAMPs can not only be used topically and systemically, but can also be delivered in an aerosolized form, opening up the potential to pursue many other indications as well. All three modes of delivery have been enhanced by Lytica’s development of novel formulation solutions. Commenting on the company’s progress since the beginning of the pandemic, CEO James LaTorre said, “The COVID-19 pandemic has delivered an unexpected benefit to our research efforts. It forced us into a period of self-reliance, which has allowed us to significantly move the dial on our antimicrobial program and to develop a much deeper understanding of how to tailor StAMP selectivity beyond the initial hits we started with.”

While Lytica’s current focus is on applying its protein engineering expertise to the creation of clinically effective StAMPs to help combat the ever-growing threat of antimicrobial resistance, the implications of its protein engineering platform goes far beyond infectious disease. “By tweaking the membrane-binding properties of our compounds, we see opportunities to lyse problematic cells selectively in other disease areas, especially oncology,” said LaTorre, “We are a lysis company after all!”

References

  1. 1.

    Mourtada, R. et al. Nat. Biotechnol. 37, 1186–1197 (2019).

    PubMed  Article  Google Scholar 

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