Kyle Rohde, PhD, an Assistant Professor in the Burnett School of Biomedical Sciences at UCF who works in infectious disease talks about mycobacterium tuberculosis and possible treatments that may be found under the sea.
Interview conducted by Ivanhoe Broadcast News in January 2018.
Do you have any infectious disease in particular that you focus on?
Dr. Rohde: My lab focuses specifically on tuberculosis or also known as TB which is caused by a bacteria called Mycobacterium tuberculosis.
I know most of our viewers have heard of TB before but probably don’t have much context for it here in the United States. Can you tell me a little bit about the disease?
Dr. Rohde: It’s a pulmonary disease that is acquired by aerosol infection. If somebody that is infected coughs or sneezes in your general direction you could be exposed and it’s fairly easy to transmit. However most people in this country aren’t particularly aware of the scope of the problem but they might be surprised to know that it’s actually the number one cause of death caused by an infectious agent, globally speaking. It’s estimated about a third of the global population is infected with tuberculosis. Thankfully most of those people are what we call latently infected so they don’t have symptoms but they’re potential carriers of the disease. There’s estimated about nine million new cases every year and it leads to about one and a half million deaths per year. It’s a significant health problem especially in areas such as sub-Saharan in Africa, Southeast Asia, Eastern Europe and places like that are where the highest incidence of this disease are so it’s a huge problem.
When it does cause symptoms what do people in these countries show?
Dr. Rohde: The main symptoms are what you would expect from a lung infection. You have lung damage so you would have weight loss and respiratory problems, sometimes a bloody cough and it’s very debilitating. It can also spread beyond the lungs and infect almost every organ in your body. It can move to the liver, to the bones, to the brain and in those cases the prognosis is particularly poor.
Any cure for it right now?
Dr. Rohde: There is. It is treatable but however one of the problems that our project is addressing is the need for better drugs. Most strains are treatable but that would involve a cocktail of multiple drugs for up to six to nine months. You’re asking people to take multiple pills every day for a very long period of time. And still that doesn’t have a hundred percent success rate even with that long of a treatment. That’s one of the main areas where we need improvement is even for those drugs, sort of the normal strains, that are sensitive to the drugs we need to try to come up with a treatment that’s shorter. Because it’s obviously a hardship for patients to take antibiotics for that long which have side effects that aren’t very desirable. On top of the fact that normal strains are difficult to treat , there’s an increasing amount of drug resistant strains of TB. We refer to those as MDR or multi drug resistant and there also XDR strains or extensively drug resistant. And there are some strains now we refer to TDR or totally drug resistant. There are some isolates that have been found where even experimental drugs are not effective. That’s a scary situation that is arising. About half a million cases per year are one of these drug resistant varieties. Our normal frontline drugs no longer work. You have to resore to second line drugs which may be IV drugs or things you’d have to be in the hospital to administer. They become very difficult to treat if it reaches that stage.
How many cases in the United States and worldwide, do you know roughly? Because it is not as much a problem but it is still a problem.
Dr. Rohde: The incidence is about four cases per hundred thousand. Three to four cases per hundred thousand. It’s because of our heath care infrastructure that the surveillance is effective to find those cases and contain them and treat them fairly quickly. It’s not as big of a problem here.
But still the patients here in the United States are facing that same issue with the drugs and with antibiotic resistant or resistant strains.
Dr. Rohde: Right. And I think a lot of it we see the cases because of the international nature of the United States. Not only folks from here traveling to places where there’s maybe a bigger problem but we’re also such a melting pot of a country so sometimes it’s the disease coming to us. Even though it’s not a huge problem within our borders, it’s sort of an ever present threat that we need to be involved in and try to solve.
I want to ask you about your research, what are you and your colleagues looking at?
Dr. Rohde: One of our main focuses is trying to play a part in finding new better drugs to treat TB. Two main goals from that are one, to find drugs that are more potent and might shorten the treatment time. One of the reasons we think it takes so long to cure a patient of TB with antibiotics is there are bacteria in the lung where they reside that become more drug resistant because they are walled off in a lesion, we call it Granuloma. It’s very difficult to get the drugs to where the bacteria are in the lung and the bacteria, the way they’re living, their lifestyle or their conditions there make them go into what we call a dormant mode. To where normal drugs are not very effective because those bacteria are hibernating. They’re not replicating any more. One of our goals is to try to find new drugs that might be better at killing these dormant, bacteria. We have a way in the lab to try to mimic the stresses that the bacteria are feeling in the human host, in the environment, to try to make them dormant. If we screen and test drugs on these sort of artificially dormant TB and find ones that are really good at killing them, we think that would be a good way, a good strategy to find drugs that would be more effective and quicker in the patient.
You guys are looking far and wide, tell me a little bit about how you started looking undersea for a solution.
Dr. Rohde: The motivation for looking at marine natural products is to test the chemical components that make up sponges or sea fans and other marine life. One motivation for that is that most of the antibiotics that we currently are using are derived from nature, are natural products. There’s a long successful track record of nature already providing the chemicals that we might use as antibiotics. And the marine environment in particular is under explored and has a high level of biodiversity. The more diversity you have in the source of drugs that you’re looking at, the more likely you are to find something novel. That’s one of our main goals is to find new drugs that kill TB in different ways than the current drugs.
What have you done, what have you found, take me through the steps.
Dr. Rohde: This project is definitely a close collaboration with Dr. Amy Wright at the Harbor Branch Oceanographic Institute right here in Florida. Her group has for years been collecting samples using robotic submarines from various exotic underwater locations. Things like sea sponges and things like that. They’re able to chemically extract the chemical bits and pieces from them and then provide those to us. We will then test these natural products as we refer to them, for ones that are able to kill tuberculosis. We actually use a strain of TB we’ve engineered to be luminescent or glow in the dark as a very sensitive way to measure, fairly easily if it’s growing or if it’s being killed by these marine natural products. That’s our role is using our expertise and capability of safely working with tuberculosis to then test these natural product compounds that our collaborator provides. And the hope is finding something that has never been discovered before that does kill TB.
How many different toxins have you tested and do you know where they’re from?
Dr. Rohde: We’ve screened about forty five hundred different marine samples. It’s a fairly large size screen. They catalog exactly what is the source organism for all of these things so that if we find something of interest they will be able to go back and look for more. That is an important part of it. When you do a large screening you end up with only so many what we call hits that do what you want them to do, which in our case is to kill dormant TB but not mammalian cells. For it to be a good antibiotic you want to kill the bacteria but not the host. That’s part of our triage or filter is we want drugs that kill the bacteria very well but don’t kill mammalian cells so they won’t be toxic then they’ll be potentially useful as an antibiotic.
What are the implications for your research, what do you see down the road?
Dr. Rohde: Drug discovery for any disease especially in tuberculosis is a very long process. We’re sort of positioned at the very front end of what we refer to as a pipeline for finding antibiotics. We’re at the very discovery stage of finding compounds that kill TB but from there to an actual drug, a lot of attrition happens along the way. A lot of hits that look interesting will never make it out the other end of the pipeline because they’re either not safe enough or not potent enough or you can’t make enough of them. The process to produce them is not scalable. That’s where we are for feeding the pipeline trying to find as many novel compounds as we can. Then it can be a ten year process to get from what we call a hit at this stage to a lead compound which is something that looks like it might be a drug. To proceed through actual clinical trials and testing can be a very long and expensive process. We’re at the very early stage of that now.
You had mentioned a time frame; could you give our viewers a sense of how long it could be before they see something that is going to work for TB?
Dr. Rohde: A best case scenario from a compound that’s at the discovery stage to even starting clinical trials we’re probably on the scope of seven to ten years. Many of the drugs that you start with will never make it even that far. The more you have at the front end of your process the more likely you are that a good drug molecule will survive and come out the other end.
You did mention that you tested forty five hundred but you didn’t say how many showed TB killing activity. How many of those look promising?
Dr. Rohde: The forty five hundred samples we started with actually contained more than that number of chemicals because they are mixtures, so each sample might have multiple potential drugs in them. We ended up with about twenty or so compounds that met our criteria for killing the bacteria but appearing to be safe for the host. Of those we were most excited about were a few that actually seemed to kill dormant TB better than replicating TB which is unusual; most antibiotics don’t work very well on dormant bacteria. We were particularly excited because this validated our approach of using a screening strategy focused on dormant bacteria. We think that allowed us to find a few that seemed to selectively target those bacteria that we think mimic the hard to kill one during infection. We were particularly excited about those and we’re working on a grant right now with a chemist. One of the challenges of natural products is there’s a limitation to how much of that sponge that is making this wonder drug that you can produce large scale. So at some point you have to have a chemist become involved that could synthesize and tweak these potential drugs. That’s our path forward: working with chemists now to be able to take it to the next step.
You said three or four, are you able to be specific on how many really show promise?
Dr. Rohde: It’s an ongoing process so in our recent publication we published our five best hits that were most well characterized and we’re still working with our collaborators to continue to purify. That’s part of the process since these are mixtures so there’s a process of purifying out the various components to find which one is the actual chemical that’s doing the killing. This is an ongoing process.
Is there anything that I didn’t ask you that you would to make sure that people take away from this?
Dr. Rohde: Not that I can think of. Is there anything you can think of?
The main thing is how many showed success in killing TB.
Dr. Rohde: That gives you the feeling you started with thousands and you end up with a couple.
People want to know the next step.
Dr. Rohde: Right. And because it takes so much effort to develop them we always have to have a very careful plan to prioritize and have various criteria to sort of try to pick what we think are the best candidates to invest the resources and the effort in trying to push forward the ones that appear to be the most potent or the most drug like.
The handful from there, what is the next step?
Dr. Rohde: The next step is that we would either work with chemist partners, to then be able to synthesize these compounds in the lab so that we don’t have to keep relying on nature to provide them. If we need to access more of these compounds we would work with chemists. Another thing that would be important is even the compounds that don’t fit the bill to become antibiotics or drugs we still plan to use those as we refer to them as just chemical tools to try to understand how are they killing the bacteria. They may not be the ideal drug but we could use them to figure out maybe a new target and then can use that information to then circle back to find a better drug like molecule to hit that target. Even the ones that aren’t the best antibiotics, it’s not a loss. We would just use them to understand new ways to kill TB.
And the plan, the hope for the consumer in seven to ten years is a drug that’s effective that is easier on them that’s going to be one compound instead of a lengthy process or hospital stay?
Dr. Rohde: Right. The dogma in the field is we don’t envision being able to use a single antibiotic because there’s higher risk of developing resistance when you’re only hitting the bacteria with one. The overall goal is a whole new cocktail – three to four new antibiotics that can work together and synergize with each other. Our aim is to decrease the treatment time to much shorter than six to nine months. And as well be effective against drug resistant strains so that we have ways to deal with those infections.
END OF INTERVIEW
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