[Editors] MIT's anti-microbial 'grammar' may mean new medicines

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
Phone: 617-253-2700
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MIT's anti-microbial 'grammar' may mean new medicines

--Custom peptides punch holes in anthrax, staph bacterial microbes
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For Immediate Release
THURSDAY, OCT. 19, 2006
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

--PHOTO AVAILABLE--

CAMBRIDGE, Mass.--In most languages, sentences only make sense if the 
words are placed in the right order. Now, MIT researchers and an IBM 
colleague have used grammatical principles to help their search for 
new antimicrobial medicines.

After identifying "grammatical" patterns in naturally occurring 
antimicrobial peptides, the researchers custom-designed molecules 
that proved extremely effective in killing microbes, including 
anthrax bacteria. The research could lead to new medicines to combat 
deadly drug-resistant bacteria.

"In the last 40 years, there have been only two new classes of 
antibiotic drugs discovered and brought to the market," said graduate 
student Christopher Loose, lead author of a paper on the work that 
appears in the Oct. 19 issue of Nature. "There is an incredible need 
to come up with new medicines."

Loose, research associate Kyle Jensen and Professor Gregory 
Stephanopoulos of the Department of Chemical Engineering are focusing 
their attention on antimicrobial peptides, or short strings of amino 
acids. Such peptides are naturally found in multicellular organisms, 
where they play a role in defense against infectious bacteria.

The researchers' newly designed peptides were shown to be effective 
against dangerous microbes such as Bacillus anthracis (anthrax) and 
Staphyloccus aureus, a bacteria that spreads in hospitals and is 
frequently drug-resistant. The peptides may also be less likely to 
induce drug resistance in these bacteria, according to the 
researchers.

Antimicrobial peptides act by attaching to bacterial membranes and 
punching holes in them, an attack that is general to many different 
types of bacteria and is difficult for them to defend against. 
"There's no quick easy mutation fix for a bacteria to get around this 
non-specific membrane attack," said Loose.

The peptides are generally short, consisting of about 20 amino acid 
building blocks. The molecules naturally fold into a helix, with 
positively charged areas running along one side of the helix and 
hydrophobic (water-resisting) areas along the other side. The charged 
ends allow the peptides to latch onto the bacteria by attracting the 
negative charges of the bacterial membrane, while the hydrophobic 
ends punch holes in the membrane.

Because there are 20 naturally occurring amino acids, there are about 
1026 possible peptide sequences of length 20. Some of those kill 
microbes with varying levels of effectiveness; the overwhelming 
majority have no effect.

With such a mind-boggling number of possible combinations, it is 
extremely difficult to find effective antimicrobial peptides by using 
traditional methods such as testing random sequences or slightly 
tweaking naturally existing peptides. "Designing them from scratch is 
quite difficult," said Loose.

Instead, the researchers decided to take a more strategic approach, 
based on grammatical patterns in the peptide sequences.

At its essence, a "grammar" is a simple rule that describes the 
allowed arrangements of words in a given language. As it applies to 
peptides, the sequence can be thought of as a sentence, while the 
individual amino acids are the words. For example, the sequence 
QxEAGxLxKxxK, where x is any amino acid and Q, E, A, etc. are 
specific amino acids, is a pattern that occurs in more than 90 
percent of a certain class of insect antimicrobial proteins known as 
cecropins.

In this case, the researchers, led by Jensen and Isidore Rigoutsos of 
IBM Research (Rigoutsos is also a visiting lecturer in the Department 
of Chemical Engineering), used a pattern discovery tool to find about 
700 grammatical patterns in the sequences of 526 naturally occurring 
antimicrobial peptides.

To design their new peptides, the researchers first came up with all 
possible 20-amino acid sequences in which each overlapping string of 
10 amino acids conformed to one of the grammars. They then removed 
any peptides that had six or more amino acids in a row in common with 
naturally occurring peptides.  Then, they threw out sequences that 
were very similar to each other and chose 42 peptides to test.

About half of the peptides displayed significant antimicrobial 
activity against two common strains of bacteria - Escherichia coli 
and Bacillus cereus. That is a much higher success rate than one 
would expect from testing randomly generated sequences, and much 
higher than the success rate for peptides with the same amino acids 
as the designed sequences, but in a shuffled order.

"We've been able to focus our shotgun approach so that half of the 
time, we get a hit," said Loose.

In further tests, two of the designed peptides showed very high 
effectiveness against two types of especially dangerous bacteria, S. 
aureus and anthrax.

The researchers have already begun using their technique to further 
refine the most effective peptides by tinkering with the sequences 
and altering traits like charge and hydrophobicity. They hope this 
process will eventually lead to new, more effective antimicrobial 
medicines.

The research was funded by the Singapore-MIT Alliance, the National 
Institutes of Health and the Fannie and John Hertz Foundation.

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By Anne Trafton, News Office