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.
Elizabeth A. Thomson | MIT News Office
Scientists discover species of dolphin that existed along South Carolina coast
24.08.2017 | New York Institute of Technology
The science of fluoride flipping
24.08.2017 | University of North Carolina Health Care
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
24.08.2017 | Medical Engineering
24.08.2017 | Earth Sciences
24.08.2017 | Earth Sciences