More than an Antibiotic: Unveiling Alternative Therapeutic Potential of Gentamicin

By Deb Chen, PhD Candidate, Devine Lab, CBR

Approximately 10% of rare genetic diseases are caused by nonsense mutations, in which a stop codon is introduced and the synthesis of the full-length protein is terminated prematurely. Alireza Baradaran-Heravi and colleagues from the Strynadka lab revealed that a minor component of the antibiotic gentamicin has the potent ability to suppress nonsense mutations to promote formation of the full-length protein. This purified component, gentamicin B1, may be of potential therapeutic benefit for many patients living with these rare genetic diseases. The paper was recently published in Proceedings of the National Academy of Sciences.

Gentamicin is an antibiotic used to treat several types of bacterial infection. Pharmaceutical gentamicin is a mixture of major gentamicins C1, C1a, C2, C2a, and C2b as well as minor related aminoglycosides, including gentamicin B1. The ability of gentamicin to enable production of a full-length protein from a gene harboring a nonsense mutation, has been previously explored; however, the dose required is often toxic to humans and the response to gentamicin treatment has shown unexplained variability.

Baradaran-Heravi et al. demonstrated that incubation of cultured human cancer cells with purified gentamicin B1 resulted in production of full-length tumor protein p53 despite a p53 nonsense mutation, while other gentamicin components did not. Gentamicin B1 also enabled formation of full-length p53 despite the presence of the nonsense mutation in a mouse model. Moreover, gentamicin B1 was able to successfully induce translation of full-length, functional proteins in a dose-dependent manner in cell lines derived from four patients with different genetic diseases.

The research team also uncovered a potential mechanism using molecular dynamic simulations of the interactions at the nonsense mutation site: It appears that gentamicin B1 enhances the elongation-like conformation of the ribosome to permit insertion of an amino acid at the premature terminal codon, thus allowing for synthesis of the full-length protein.

As the presence of other gentamicin components appears to dampen the ability of gentamicin B1 to facilitate translation at the premature stop codon, purified gentamicin B1 offers great promise as a viable therapeutic agent for rare genetic diseases.

 

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