Berserker Molecule: Targeting Lyme Treatment?

Cell Chemical Biology (Carlson, D.L., et al.) 11.01.2023 published online “Targeting Borrelia burgdorferi HtpG with a berserker molecule, a strategy for anti-microbial development.” Researchers have found that by targeting a non-essential enzyme, Borrelia burgdorferi HtpG, they are able to expand what is considered “druggable” in any pathogen, effectively killing Lyme bacteria.  

Hsp90 inhibitors (heat shock proteins) are an example of non-essential bacterial proteins that contain a susceptible target. Many have been extensively tested in clinical trials for cancer treatments, and have also been evaluated as novel therapeutics in yeast and parasite (malaria and Leishmania) studies.

Researchers have now synthesized HS-291, which is an HtpG inhibitor (a non-essential bacterial protein that contains a desirable druggable domain) tied to verteporfin, which is a photoactive toxin. Borrelia cultures are sterilized by HS-291 through oxidation of HTpG, and the result of this oxidation process is “nucleoid collapse and membrane blebbing” of the pathogen, which results in cellular death.

When light activated, a single dose of HS-291 is found to be a “berserker” molecule that completely disrupts the biology of the Lyme bacteria and irreversibly damages the proteins close to B. burgdorferi HtpG. This is a targeted strategy that may lead to development of antimicrobials that not only eradicate the pathogen, but also counteract potential antibiotic resistance.

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