Good morning, everyone.

Well, first of all, I would like to thank the organizers for giving me the opportunity

of being presenting today this project in which I've been involved now for three years

as a postdoc at the University of Glasgow in UK.

Well, two years ago when this conference was running in Lethbridge, Canada, I presented

this work and, you know, I received a very nice feedback from the audience, questions,

suggestions.

So it's great to be back after two years showing you how the project has progressed and also

how we include some of the suggestions that we receive.

Well, to put you in context, the model organism of this project is entero-morrhagicicolai,

so also called Ihec.

So these bacteria asymptomatically colonize cattle, but then from cattle can be transmitted

to humans through undercooked meat, but also contaminated water or even contaminated lettuce

leaves.

And in humans, these bacteria produce bloody diarrhea, hemorrhagic colitis and the hemolytic

uremic syndrome.

So you can imagine how bad these bacteria infections are.

And the problem is that there are no vaccines currently available against Ihec and also

the antibiotic treatment is contraindicated for these kind of infections because these

bacteria produce a toxin and in the present of antibiotic, basically the bacteria produce

more and more toxin, would increase the severity of the disease.

So this is the reason why the main aim of this project was to try to develop an alternative

strategy to the use of antibiotics to treat Ihec infections.

So instead of use a traditional antibiotic that kill the bacteria or inhibit the bacteria

growth, the idea was to try to develop compounds, chemical entities, able to inhibit the expression

of virulent genes in Ihec.

Because imagine if a pathogenic bacteria is not expressing virulent genes, would be less

virulent or even avirulent and more accessible for the immune system.

So in 2011, it was published that there is a family of compounds, the SA compounds, and

these compounds inhibit the expression of virulent genes in Ihec.

Specifically, these compounds inhibit the expression of the Ti3 secretion system genes.

This is the system that the bacteria use to colonize the host.

Interestingly, even though several proteins are involved building the system, none of

the proteins of the system are the target of the compounds.

The protein target of these compounds is an enzyme called ADHD, which converts acetyl-CoA

to ethanol.

So our hypothesis is that these compounds are somehow affecting the protein and in consequence

the metabolism controlled by this enzyme is altered.

And the alteration in the metabolism is what as a final consequence somehow is inhibiting

the expression of virulent genes in Ihec.

But to understand the effect of the compounds on this enzyme, first we need to know who

ADHD is.

So as I commented before, ADHD is an enzyme.

Here what I'm showing is the structure of the monomer.

And as you can see, the monomer has two domains.

The N-terminal domain is aldehyde dehydrogenase, which converts acetyl-CoA to acetaldehyde,

whereas the C-terminal domain is an alkyl dehydrogenase that converts acetaldehyde to

ethanol.

But this enzyme is bidirectional, so that means that also can convert ethanol to acetyl-CoA.

So interestingly, this is the monomer, but interestingly in the bacteria, this protein