Christopher Bunick, MD, PhD, Previews Recently Published Sarecycline Study to be Presented at AAD

A newly published study¹ in Nucleic Acids Research explored sarecycline’s ability to inhibit protein translation in Cutibacterium acnes (C. acnes) 70S ribosome using a 2-site mechanism. Christopher Bunick, MD, PhD, FAAD; Ivan B Lomakin, PhD; Swapnil C Devarkar, PhD; Shivali Patel, PhD; and Ayman Grada, MD, MS, sought to prove how sarecycline, a 3rd generation tetracycline-class antibiotic, works differently and is more beneficial than other tetracycline-class antibiotics for treating acne vulgaris. Bunick, physician-scientist and associate professor of dermatology at Yale School of Medicine, spoke with Dermatology Times® to preview the breakthrough data he will be sharing for the first time publicly at the American Academy of Dermatology (AAD) Annual Meeting, March 17-21, 2023, in New Orleans, Louisiana.

For an in-depth discussion of the recent sarecycline study, Bunick will present findings from Lomakin et al at the Acne Boot Camp Session at AAD on Saturday, March 18th from 3:30 PM - 5:30 PM CDT. During the session, Bunick will also speak alongside Emmy M Graber, MD, MBA, FAAD; Bethanee Jean Schlosser, MD, PhD, FAAD; and Joshua Zeichner, MD, FAAD, to discuss the latest updates in effectively treating patients with acne vulgaris.

“I invite you to come out to this Acne Boot Camp Session. I’m going to be talking publicly for the first time about this new Cutibacterium acnes cryo-EM structure, which was done in my laboratory and led by first author Ivan Lomakin. I’m going to talk about this structure and other aspects of antibiotic use in dermatology, including blood-brain barrier penetration, adverse events, the microbiome, and how we can use antibiotics with proper antibiotic stewardship going forward,” Bunick concluded.

Reference

1. Lomakin IB, Devarkar SC, Patel S, Grada A, Bunick CG. Sarecycline inhibits protein translation in Cutibacterium acnes 70S ribosome using a two-site mechanism, Nucleic Acids Research, 2023; gkad103, https://doi.org/10.1093/nar/gkad103

Transcript:

Christopher Bunick, MD, PhD: I'm Christopher Bunick, associate professor of dermatology and physician scientist at Yale University. I'm really excited to share some exciting news out of my research laboratory, where we've just recently published a paper looking at the Cutibacterium acnes ribosome structure by cryo-electron microscopy (EM). This work was published in Nucleic Acids Research and determining the high-resolution structure of the Cutibacterium acnes ribosome has opened the door for really understanding acne therapy at a new level. If we think about acne therapy over the last 50 years, oral antibiotics are a pretty commonplace treatment for moderate-to-severe inflammatory acne. We commonly think that the tetracycline family of antibiotics, which are prescribed at almost 75% rate of all the oral antibiotics we do in dermatology, we think we really understand how they work. But the truth is that we've never actually understood how they work in their target organism. So clinically, when we're treating acne with antibiotics, we're actually targeting Cutibacterium acnes because dermatologists believe that Cutibacterium acnes plays a significant role in the pathogenesis of acne vulgaris.

So what our laboratory's cryo-EM structure of the Cutibacterium acnes ribosome does is for the first time it actually captures an oral antibiotic, sarecycline, which is a tetracycline derived antibiotic. It captures sarecycline bound to the 70S ribosomes of the pathogenic target. And what we discovered was that there are actually 2 binding sites, not one. Historically, it was thought that tetracycline derivatives would bind in a specific location known as the decoding center of the ribosome, where the ribosome is reading messenger RNA to translate it into protein. And indeed, we see that sarecycline does bind there. And what we found in the C. acnes cryo-electron microscopy structure was actually there was a second finding site in what's called the exit tunnel of the ribosome, where the growing protein, the protein that's being made by the ribosomes, is exiting through the ribosomes itself.

This is actually a pretty fundamental discovery that there are actually 2 active sites where sarecycline is functioning on Cutibacterium acnes ribosome. Why is this important for clinicians? Well, when we're treating patients with oral antibiotics, we know that there are a couple of common things that we think about. Number one: side effects such as GI disturbance. Number 2: we think about antibiotic resistance. And in dermatology, antibiotic stewardship is a pretty important topic. Sometimes it gets swept under the rug, but it doesn't need to be swept under the rug, it needs to be tackled with science. And our structure does that because if you think about having 2 sites where an antibiotic binds, if you have a ribosomal mutation in one site, that's not going to be enough to create antibiotic resistance; you need a dual-site mutation in order to create antibiotic resistance with sarecycline, based on our scientific data. This actually correlates with a lot of the clinical trial data showing that sarecycline has some of the lowest rates of antibiotic resistance of any of the antibiotics that we commonly use in our patients. So here's a real correlation between a scientific finding of how the drug is binding in 2 locations, correlating to a low risk of antibiotic resistance. And so in dermatology, if we want to promote antibiotic stewardship, focusing on a narrow spectrum agent like sarecycline, meaning it has really a preference for gram-positive organisms over gram-negative, this is going to help limit antibiotic resistance, and it's going to protect the gut microbiome, something that we're very interested in doing for our patients so they don't end up with a lot of GI upset, or some of the more long-term complications that come from broad spectrum antibiotics.

Other aspects of our structure that are really important are that we found some new extensions and proteins within the Cutibacterium acnes ribosomes that really show that this bacterium has the capability to have some different functions than other species of bacteria. And we look forward to investigating more of how that is going to play out in the skin. But one of the things that was an interesting finding was this Cutibacterium acnes actually has some zinc-free and zinc-bound forms of some ribosomal proteins. And the current thought is that maybe that zinc-bound forms actually are more susceptible to antibiotics. So, if you don't have zinc for these ribosomal proteins, the zinc-free form of the Cutibacterium acnes ribosomes actually can go into what's called a hibernating state. And the thought is that if this happens, then the bacteria is actually going to be a little bit less sensitive to the antibiotic that you're trying to treat your patient with. So, this is a potential mechanism where the lack of zinc may allow bacteria to escape treatment from antibiotics and may actually promote antibiotic resistance. So I think that further investigation into the role of zinc and enhancing the efficacy of antibiotics and acne therapies is warranted based on the science that we've discovered.

One of the interesting things about sarecycline’s chemical structure is it has this unique, what's called a C7 moiety, a long extension on carbon position 7 on ring D of the 4-ring tetracycline backbone structure. We also published another paper recently about how this C7 moiety decreases the lipophilicity of sarecycline, which actually in turn reduces the blood-brain barrier penetration of the medication. What we found in this particular study was that the sarecycline compared to minocycline, sarecycline did not cross the blood-brain barrier of rats, whereas minocycline did. Why is this clinically important? Well, when we're treating our patients with minocycline, it’s wellknown that minocycline can cause vestibular side effects such as vertigo or dizziness. In fact, this is so commonplace that the United States military bans its aviators from using minocycline because of its vestibular disturbance risk. So our study shows that this unique chemical structure of sarecycline reduces its ability to cross that blood-brain barrier. Therefore, it correlates with the clinical trial studies where sarecycline had very, very little or low rates of vestibular disturbances. 

I'm going to be speaking in the Acne Boot Camp Session at the American Academy of Dermatology Meeting in New Orleans, Louisiana, in just a week or so. I invite you to come out to this Acne Boot Camp Session. I'm going to be talking publicly for the first time about this Cutibacterium acnes cryo-EM structure, which was done in my laboratory and led by first author Ivan Lomakin. I'm going to talk about this structure and other aspects of antibiotic use in dermatology, including blood-brain barrier penetration, adverse events, the microbiome, and how we can use antibiotics with proper antibiotic stewardship going forward. Thank you.

[Transcript edited for clarity]