Sarecycline, a drug approved for use in the United States in 2018, is the first new antibiotic approved to treat acne in more than 40 years. Now, researchers at Yale and the University of Illinois-Chicago have discovered how its unique chemical structure makes it effective.
Their new study is the most detailed biological analysis to date for sarecycline, one of a number of tetracycline antibiotics (such as doxycycline and minocycline) used to treat acne. The researchers report findings today (August 3, 2020) in Proceedings of the National Academy of Sciences.
They found that unlike other tetracycline drugs, sarecycline binds to messenger RNA (mRNA) — molecules within a cell that provide a code for making proteins — in bacterial ribosomes. Ribosomes, found in all living cells, link
Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called “essential” for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.
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Sarecycline and other tetracyclines treat acne by inhibiting bacterial protein synthesis. They block ribosome function in Cutibacterium acnes, the pathogenic bacterium in acne.
“We show that the structure of sarecycline matters,” said Dr. Christopher Bunick, associate professor of dermatology at Yale and co-corresponding author of the study. “This mode of action has never been seen before in this class of antibiotics, and suggests that sarecycline has unique properties among the tetracycline class.”
Importantly, the researchers found an explanation for why sarecycline has such a low drug-resistance profile, boosting its effectiveness. Sarecycline thwarts TetM, a ribosome guardian protein that protects bacteria from outside interference.
Bunick and his team said the broader implication of the study is that structural knowledge of tetracycline compounds could be used to engineer better antibiotics.
“This could result in therapies with better or longer-lasting efficacy, fewer side effects, and lower drug resistance,” Bunick said. “Future agents could be used not just in acne, but potentially in other skin disorders and infections as well.”
Reference: 3 August 2020, Proceedings of the National Academy of Sciences.
The co-corresponding author of the study was Yury Polikanov of the University of Illinois-Chicago. Zahra Batool of UIC was first author of the study and Ivan Lomakin of Yale was a co-author.
The National Institutes of Health, State of Illinois startup funds, and a research grant from Almirall funded the research. Bunick has received honoraria for consulting and speaking for Almirall.