Authors: Jenn Edwards (Abigail Wexner Research Institute, OH, USA)
Antibiotic resistance in gonorrhea has been an area of growing concern across the past couple of years, but could there be alternatives to these drugs for treatment and prevention? In this interview, we speak to Jenn Edwards from the Abigail Wexner Research Institute (OH, USA) about her research using the primary human epithelial cell models to examine Neisseria gonorrhoeae infections, the potential for vaccination against gonorrhea and a possible host-targeted therapy for this infection.
First, can you introduce yourself and tell us a bit about your background?
So, I was a non-traditional student – I went back to school as a single mom of three in my 30s, did my undergraduate and master’s in a small liberal arts college in Northern Minnesota. I then went to the University of Iowa (IA, USA) where I trained with Mike Apicella. From there, I moved to Ohio and joined the Abigail Wexner Research Institute at Nationwide Children’s Hospital in 2004.
Why is drug-resistant gonorrhea an area of particular concern?
Essentially, we are running out of ways to treat it. This bug is notorious for its ability to develop resistance mechanisms and it is also highly human adaptive, so it is very difficult to not only find ways to treat it but also to find ways to prevent it, and obviously we are a few years at least away from the vaccines. In light of this, finding different antimicrobials that might actually work against drug-resistant gonorrhea is critical right now.
Would you say cases are increasing?
They are increasing. I know there has been an 80% increase in Australia since 2009 and a 75% increase in the United States since 2009. So, cases are on the rise and it is only going to get worse with the emergence of more untreatable strains.
Why do you think vaccines are a valuable option?
Well, as I just mentioned, even if we do develop new antibiotics, they are probably only going to be a short-term solution. The only true way to eradicate this bacteria is through a vaccine.
How do you think understanding the host–pathogen interaction could help identify new diagnostics and new treatments?
I think this is a critical area of research. You can’t solve the problem if you don’t fully understand it, and although there have been some scientific discoveries that have been serendipitous, for the most part all major scientific breakthroughs come through the work of many, many researchers over many, many years.
As one example of how host–pathogen interactions could translate to treatment options, in our work many years ago we identified this host molecule termed complement receptor three (CR3), which is present on the cervical cell surface. We identified that CR3 serves as the major receptor by which the bacteria invade the cervix and we are now using that information to develop a new host-targeted approach to treating gonorrhea. I think a host-directed therapy for gonorrhea is a really promising strategy because of the pathogen’s ability to manipulate the host and develop resistance.
Are there any candidates for the treatment of gonorrhea you feel particularly optimistic about?
So, there are three traditional antibiotics in the pipeline, which all show promise, and they are in various stages of clinical trials. However, these new, traditional antibiotics are probably only a short-term solution.
We have taken an alternative approach and we have actually identified two drugs that can be repurposed; one is carbamazepine, which is used to treat epilepsy; the other is methyldopa, which is used to treat gestational hypertension.
What we have discovered using our cell culture model, which is primary human cervical epithelial cells, is that we can get a 100% cure of an established infection by blocking this interaction that the bacteria have with the cervical cell surface, and that includes the multi-drug resistant, ‘untreatable’ strains. So, we are excited about that!
We have also seen with targeting the host, there is absolutely no resistance – you can do sequential infections and bacteria are still susceptible.
And is repurposing drugs is an easier strategy starting from scratch?
Yes definitely. It can fast track them into clinical use because they are already US FDA approved, they already have established safety profiles and the pharmacokinetics are all already known. Moreover, for the two drugs we have identified we have actually been using them at doses that are below the normal recommended doses.
What research do you think we should do in the next 5–10 years to stimulate progress?
I think, first of all, there has been a lot of recent interest in vaccine development and development of new antibiotics but I think we also need to put more focus on basic research because, as I mentioned earlier, you can’t solve the problem if you don’t know what the problem is.
We need to develop better models, for example, humanized mice models using human source materials and multi-organ chip models, then we need to get more specimens from humans and assess how those correlate to what we are finding in the lab. I think there needs to be just as much emphasis on the basic research as it there does in finding a new antimicrobial or a new vaccine candidate.
Finally, is there anything else you would like to add about your research?
Just that scientifically gonorrhea it is a fascinating organism and that we are really excited about this host-targeted approach – it has just been really exciting to see it evolve over the years!
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