Christopher G Bunick, MD, PhD
Yale University
Department of Dermatology
New Haven, CT
2023 Research Scholar Award Recipient
Characterization of novel tetracycline-class compounds that target the Cutibacterium acnes ribosome
Abstract
For decades, oral antibiotics have played a central role in the treatment of acne vulgaris (AV) because of their purported anti-bacterial and anti-inflammatory activities. However, problems related to antibiotic resistance3, broad-spectrum activity, and side effects of these antibiotics have led to increased scrutiny of their role in AV therapy. Emphasis on antibiotic stewardship in clinical medicine necessitates that specific knowledge gaps surrounding antibiotics in AV be addressed, including: (i) how do antibiotics function in their clinical target, skin-pathogenic bacteria?, (ii) what are the biochemical determinants of broad vs narrow spectrum selectivity?, (iii) what are the molecular mechanisms driving antibiotic resistance?, and (iv) how can we engineer effective but safer antibiotics?
The Bunick laboratory over the past 3 years has been at the forefront of answering these questions, specifically with respect to tetracycline class antibiotics. We focus on tetracyclines for a very practical reason: tetracyclines account for ~75% of all antibiotic prescriptions in dermatology, including for AV. The class of molecules has evolved from first- (tetracycline, TET) and second-generation (doxycycline, DOX; minocycline, MCN) broad-spectrum agents to a third-generation narrow-spectrum agent (sarecycline, SAR) approved for treatment of AV in 2018. We believe, therefore, that research into the fundamental mechanisms of action of tetracycline antibiotics is essential to advancing the treatment of AV into a more pathogen-focused, precision medicine era.
Our main hypothesis for this proposal is that a novel compound can be identified that is specifically and highly targeted to C. acnes with greater protein translation inhibition than currently existing tetracyclines.