Professor Tim Bugni on transforming drug discovery for infectious diseases

Professor Tim Bugni on transforming drug discovery for infectious diseases


It is my pleasure now to introduce
some very special people so as Chancellor Blank said you know one of
the things we love about the university are the people that we have on campus
and tonight we’re gonna have the privilege of hearing some from some of
our very best who are transforming healthcare. The faculty members with us
tonight are shaping and expanding our understanding of the field of medicine
and they’re making discoveries and developing new insights into how we
treat infectious diseases, how we care for aging adults, and how we alleviate
suffering and save lives through transplant surgery.
Barbara Bowers, Tim Bugni, and Robert Redfield are changing lives with their
work in the breadth of their involvement with research, education, and outreach, and
the depth of their expertise exemplify the importance of faculty to a public
research institution like ours. Ladies and gentlemen, please welcome Professor Tim Bugni of the UW-Madison School of Pharmacy. First off, I’d like to just extend a warm welcome to all of you tonight. It’s a
little bit unusual but I’m actually working off a script tonight, but
apparently my understanding is scripts are quite good at suppressing a
long-winded phenotype of some scientists, so we’ll see if that works
tonight. But now, more seriously, what I’d like to discuss tonight is
drugged multi drug-resistant infectious disease, and part of the driving
force for me discussing that is that we’re on the verge of a public health
crisis. So I’d like to just start from this point which is an article from
the Scientific American in 2017 and it’s really highlighting the fact that a
woman died from an infection that was resistant to 26 different antibiotics.
There’s a there’s a couple of important points that come to mind here,
and one is that we now encounter infections that are resistant to all
available antibiotics. Two is that the pipeline for new drugs really lacks the
chemical diversity to overcome this resistance. There are
predictions now that suggest that we’re looking at maybe 10 million deaths annually by the year 2050 from drug-resistant infectious disease
based on our current trajectory. So my research team is really, what
we’re trying to do is change that trajectory. Another thing that
was published in 2017 was a report from the World Health Organization, and
this report highlighted two aspects. One is it really talked about the most
important critical drug-resistant pathogens out there. The other thing that
this article did is really outlined and investigated the clinical pipeline,
and the World Health Organization found some fundamental issues with the
the drug pipeline as it exists today and the problem is that that pipeline lacked
chemical and structural diversity. In other words, many of the molecules
in there basically looked rather similar to antibiotics that we’ve used in the
past and this presents a situation where we’re going to observe resistance much
more quickly than say if those molecules look completely different and had
completely different mechanisms of the action. So this brings about what I’m focused on in research, and the idea is that if we could find new
molecules with new mechanisms of action we’re gonna have a much higher
likelihood of overcoming resistance, so my focus in my research program is
really identifying new chemical diversity from nature. So first off
I’d like to step back for a second and just talk to you a little bit about
where antibiotics come from. About 75% of all antibiotics, actually, the molecules
can be traced back to having origins in filamentous bacteria such as the one
shown here, which is Streptomyces coelicolor. Members of the genus of
Streptomyces have been cultivated from soil samples around the whole globe and
these have been thoroughly investigated for antibiotics. The problem
today, it’s not that there aren’t new antibiotics that you could get from
these organisms, the fundamental issue is that you have to look at 100,000 of
these to a million different bacteria to find one new molecule, and if you
know anything about drug development, most drugs fail in the development stage
so at the end of the day this is just simply an unsustainable practice. On the
other hand, my lab has discovered three new classes of molecules from
investigating as few as 36 bacteria from marine ecosystems.
Really what this says to us is that the marine
environment and this new ecological niche represents one pathway to
discovering new chemical diversity. So how did I end up studying marine
bacteria? I’d like to segue a little bit into my journey with regard to
studying marine bacteria. The structures here highlight aspects of
that journey both structures demonstrate incredible chemical architecture. That of
course intrigued the chemist in me. Both of these agents are actually clinically
approved anti-cancer agents that were discovered from marine invertebrates.
The issues surrounding chemistry for marine invertebrates is
that it’s really really difficult to get sufficient quantities to go through the
development pipeline. It’s simply impossible to go out and collect enough
of these animals off of a reef to actually get enough of the molecules.
However, over the past 20 years, what research has shown is that molecules
such as these are actually produced by symbiotic microorganisms within the
whole marine animal. In fact yondelis that’s shown up here,
the precursor is actually manufactured through fermentation of a bacterium,
really solidifying the roots of this molecule being produced in the whole
animal by a bacterium. As a result I wanted to investigate the symbiotic
bacteria in marine invertebrates when I started my lab here at UW. So my lab,
actually we go out, we sample marine invertebrates such as the one shown here,
and we cultivate bacteria from these invertebrates for the purposes of drug
discovery. It’s been one fundamental question driving technology development
in my lab and really that question is how can we assess and model the chemical
diversity from these bacteria and really analyze this in a much deeper
sense. The answer to that question if
you think about what I mentioned with regard to the World Health Organization
also answers some of the problems associated with the current clinical
pipeline: We need more chemical diversity. Over the past nine years my
laboratory has worked on technology development to assess and to mine
chemical diversity for marine bacteria. I’m not going to get into too
great a detail about how we do this but just to give you a little flavor of what
we do our approach uses high performance liquid chromatography, or HPLC. This
allows us to separate the molecules that we isolate from the bacteria and then we
we use that in conjunction with mass spectrometry, so essentially we use HPLC
to separate all the molecules from the bacteria and then we analyze each of
those molecules by mass spectrometry, and mass spectrometry today gives us such
accuracy with the measurement of the masses of these that we can actually say
something about the chemical composition. So now you can envision that we can use
computers to go through analyze these data, pick out the compounds, we know
something about the chemical composition, and now we can apply statistical models
to the data and really find bacteria that are you know statistical outliers,
something that really stands out, we get some signature that tells us, hey look
this bacterium is really different than the rest, let’s have a look at that.
One of the most interesting bacteria that we found today we
discovered through this process and it was a bacterium isolated from this
marine invertebrate shown here which is called Ecteinascidia turbinata and
what is important about this bacterium is that we discovered it from analyzing
again only 36 different bacteria, that’s in contrast to the hundred thousand or
million that would have to be assessed using traditional methods. One of the
interesting molecules we found from this this bacterium that came from this
invertebrate was a molecule that we named forazoline,
and forazoline was a new antifungal agent and also had a new
mechanism of action and an incredibly interesting structure. These are the
types of features that we think are necessary to overcome current clinical
resistance. So we could apply our methods to marine bacteria. We’ve been able to discover agents in an anti microbials at a significantly higher rate compared to traditional approaches. However, we’re always limited in
comparison to the number of bacteria that we could actually cultivate. We
always felt that we really need to analyze all of the bacteria that we have.
So I had some ideas because we were sitting at a point where we could
analyze groups of about 30 to 50 bacteria reasonably well, but we had
thousands in the lab we could cultivate thousands of interesting bacteria, and
how are we gonna analyze all these. So this was really the critical juncture
I think in terms of building a sustainable discovery pipeline. And
I had some ideas about how we might do this but but there were some challenges
going forward with that. Finally I got the right graduate student and a
graduate student by the name of Shaurya Chanana joined my lab and he was
really interested in programming, and so I was able to talk to him about my ideas
and you know discuss these ideas and he was actually able to go in write
programs to do what I wanted to do and actually build this pipeline and it and
this has only happened in over the course of the last few months. But now we
can actually analyze thousands of bacteria, which I think will generate a
pretty sustainable pipeline at least for the near future. So the grand
question of course is how does this really impact the drug pipeline are we
seeing a number of molecules with promising activity in in vivo models.
To answer that question we’ve evaluated a number of the molecules that have been
discovered for my program in animal models of infectious disease, and out of
61 that we’ve tested, 36 of those showed some effect in
animals, many showed impressive activity against either our model fungal pathogen,
Candida albicans, or our model gram-negative pathogen, E.coli.
The data shown behind me here indicate a measure of how well the
molecules work by measuring the number of colony-forming units that are in the
animal after treatment with either an antibiotic or an antifungal agent.
On the plot behind me there’s a line through the center that’s the group that
it has been has not been treated with anything, so that gives you the
baseline. All of the dots and the data below that line are representing
molecules that show efficacy in an animal model and really what this data
shows is that we have a large number of molecules, many of them showing
significant in vivo efficacy against some of these really nasty pathogens. I’d
just like to mention that the data generated here was done in collaboration
with Dr. David Andes. David is the chair of the Department of Infectious Diseases
here in the medical school. It’s also worth noting that the animal models for
infectious disease actually recapitulate efficacy in humans quite well.
Finally I would like to just highlight results from a molecule that is further
along in our pipeline, currently moving forward on patenting a molecule that we
named turbomycin, and turbomycin is effective against the fungal pathogen
named Canada Oris, also known as the killer fungus, this is a really
nasty pathogen and the particular strain that we use to generate these data is
resistant to all currently available, all clinically available
anti-fungal agents, so it’s essentially untreatable. What we found is turbomycin is highly effective in a mouse model and reduces colony forming units
in the mouse model, the blue bars behind me, by almost three logs.
When we look at these data, we think of a one log reduction as being
fairly effective so we’re seeing a 3 log reduction with this molecule, so as a
result turbomycin is a highly promising therapeutic for an infection
that results in 90 percent or greater mortality rate in the clinic.
What’s important here is this discovery was driven by our fundamental work on
mining models of chemical diversity from marine bacteria. In summary I think
just like say that you know we’ve we’ve come a long ways in terms of overcoming
these critical barriers in the fight against drug-resistant infectious
disease through a combination of unique bacteria from the marine environment and
analytical technology development. With that I’d just like to thank you all for
your attention tonight.

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