Team:Goettingen/Project/Outlook

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===Outlook===
===Outlook===
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We made it. The systems worked! Applause for everyone's hard work! However, there are still some bugs needed to be fixed before the reporter systems become really "perfect".
 
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Right now, both our systems are working "too" well. They cannot give a quantitative output of how effective a substance is. They are only able to say just YES or NO, ON or OFF.  But we still believe that this is already a great success and good news to us.
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Worldwide, the number of antibiotic resistant bacteria is increasing, while the development of new antibiotics is still stumbling.  Therefore, we intended to build a reporter system to screen for antibiotics directed against cyclic di-AMP, an essential signaling nucleotide found in many Gram-positive bacteria.  
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What can we do with them now? When Prof. Dr. Stephen Benkovic  visited Göttingen this summer, he promised to screen his substance library with our systems. And that is exactly what our systems are for: to screen huge numbers of substances on their ability to turn the lights off. Prof. Dr. Stephen Benkovic's promise is only our first step, with further improvement, our systems will be finally applied in pharmaceutical industries, play the role they should play. Cooperate with Green Coli and save the world with him!
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We applied the Gram-negative bacterium ''E. coli'' , which has no endogenous c-di-AMP, as a carrier organism. We used several existing Biobricks and recently discovered c-di-AMP sensors from ''Bacillus subtilis'' or ''Mycobacterium smegmatis'', We managed to construct two ''in vivo'' screening systems based on different principles. Though these systems still need improvement, they were active and partially functional in ''E. coli''. Thus, we plan to optimize these systems for further development. Once these systems are fully functional, one could provide ''E. coli'' with c-di-AMP by co-expressing its biosynthesis enzyme, a diadenylate cyclase(Fig. 1). Such an ''in vivo'' screening system could be used to screen effectively for novel antibiotics.
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What else is possible with our results you might ask: With the 3D structure of the DAC domain known, bio-informatics all over the world can start designing novel substances which may interfere with the DAC domain and thereby interfere with the c-di-AMP homeostasis in Gram-positive pathogens.  
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As c-di-AMP homeostasis plays a vital role in many Gram-positive bacteria, its biosynthesis enzyme, diadenylate cyclase (DAC), becomes a very promising target for novel antibacterial substances. We worked on the characterization of one DAC from ''Listeria monocytogenes''. We were able to obtain the crystal structure with the help of the department of Structural Biology and determined a 3D-structure out of it. With this structure known, ''in silico'' screenings for novel antibiotics which could disturb this enzyme could start. The purified DAC could also be employed for ''in vitro'' screenings.
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We have big hopes that our work on this project may contribute to stop our world falling back into the dark ages, when the plague eradicated one third of the population of Europe.
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https://static.igem.org/mediawiki/2013/f/f2/Goe-overview-fig1.png
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At last we would like to invite next year’s iGEM teams, not only the iGEM Team Göttingen 2014, to work on our construct and improve it further.  
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'''Fig. 1.''' For ''in vivo'' screening for new antibiotics, the DAC could be cloned into an ''E. coli'' cell harboring a reporter system. The crystal structure of the DAC could be used for ''in silico'' screening. The purified enzyme can be used for ''in vitro'' screening.
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Keep the green light glowing!
 
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<html><img src="https://static.igem.org/mediawiki/2013/8/8c/Goe-greenColi-transparent.png" class="fr" height="300" /></html>
 
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Hello my dear friends,
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my name is Green Coli. Five months ago, I was just a normal ''E. coli''. Sounds incredible, yeah? Just five months, I have became a super hero!  A super hero willing to save the world from multi-resistant bacteria. Thanks to 2013 iGEM Team Goettingen!
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They have constructed a simple, but very powerful weapon for me. It’s an antibiotic detector. With this detector, I can find new antibiotics targeting c-di-AMP, the achilles heel of my enemies. In my fight against those bacteria, I even found a dedicated assistant, Blue Coli who has also reporter system from <i>B. subtilis</i>. The first tests of our weapons gave us good news, but only at the moment, we’re in a small crisis, you know, as most super heroes are from time to time. Our gears are kind of out of control: mine seems to be always dark, while detector of my assistant, Blue Coli, is glowing all the time. Luckily, my helpers already have lots of ideas how to improve the system so that, soon, I and my assistant will be able to save the world again.
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In brightest day, in darkest night,
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No pathogen shall escape my sight.
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New antibiotics I will find,
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My enemies forever I bind!
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<strong style="color:green">Keep the green light glowing! </strong>
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<img src="https://static.igem.org/mediawiki/2013/8/8c/Goe-greenColi-transparent.png"  height="300" style="margin-left: 400px;margin-top: -150px;" />
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Latest revision as of 18:52, 28 October 2013





The beast and its Achilles heel:

 A novel target to fight multi-resistant pathogenic bacteria



Outlook

Worldwide, the number of antibiotic resistant bacteria is increasing, while the development of new antibiotics is still stumbling. Therefore, we intended to build a reporter system to screen for antibiotics directed against cyclic di-AMP, an essential signaling nucleotide found in many Gram-positive bacteria.

We applied the Gram-negative bacterium E. coli , which has no endogenous c-di-AMP, as a carrier organism. We used several existing Biobricks and recently discovered c-di-AMP sensors from Bacillus subtilis or Mycobacterium smegmatis, We managed to construct two in vivo screening systems based on different principles. Though these systems still need improvement, they were active and partially functional in E. coli. Thus, we plan to optimize these systems for further development. Once these systems are fully functional, one could provide E. coli with c-di-AMP by co-expressing its biosynthesis enzyme, a diadenylate cyclase(Fig. 1). Such an in vivo screening system could be used to screen effectively for novel antibiotics.

As c-di-AMP homeostasis plays a vital role in many Gram-positive bacteria, its biosynthesis enzyme, diadenylate cyclase (DAC), becomes a very promising target for novel antibacterial substances. We worked on the characterization of one DAC from Listeria monocytogenes. We were able to obtain the crystal structure with the help of the department of Structural Biology and determined a 3D-structure out of it. With this structure known, in silico screenings for novel antibiotics which could disturb this enzyme could start. The purified DAC could also be employed for in vitro screenings.

Goe-overview-fig1.png

Fig. 1. For in vivo screening for new antibiotics, the DAC could be cloned into an E. coli cell harboring a reporter system. The crystal structure of the DAC could be used for in silico screening. The purified enzyme can be used for in vitro screening.



Hello my dear friends,

my name is Green Coli. Five months ago, I was just a normal E. coli. Sounds incredible, yeah? Just five months, I have became a super hero! A super hero willing to save the world from multi-resistant bacteria. Thanks to 2013 iGEM Team Goettingen!

They have constructed a simple, but very powerful weapon for me. It’s an antibiotic detector. With this detector, I can find new antibiotics targeting c-di-AMP, the achilles heel of my enemies. In my fight against those bacteria, I even found a dedicated assistant, Blue Coli who has also reporter system from B. subtilis. The first tests of our weapons gave us good news, but only at the moment, we’re in a small crisis, you know, as most super heroes are from time to time. Our gears are kind of out of control: mine seems to be always dark, while detector of my assistant, Blue Coli, is glowing all the time. Luckily, my helpers already have lots of ideas how to improve the system so that, soon, I and my assistant will be able to save the world again.

In brightest day, in darkest night,

No pathogen shall escape my sight.

New antibiotics I will find,

My enemies forever I bind!

Keep the green light glowing!

 

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