Colleen T. O’Loughlin, Laura C. Miller, Albert Siryaporn, Knut Drescher, Martin F. Semmelhack, and Bonnie L. Bassler (2013) 110:17981–17986, doi:10.1073/pnas.1316981110
A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation
Quorum sensing is a way a bacterium communicates to the cells around it to regulate behavior of the community as a whole. This process occurs in harmless bacteria as well as pathogens. One such pathogen, Pseudomonas aeruginosa, uses quorum sensing to attack its host in a concerted effort by all the cells present and to control how the cells ‘stick’ together once infecting the host. In an effort to prevent P. aeruginosa attack and infection, researchers tested synthetic molecules to identify those which block cells from receiving the attack message. One such molecule, meta-bromo-thiolactone (mBTL), succeeded in blocking the message and protected a roundworm model system and human lung cells from dying due to infection. The paper also discusses how mBTL works at the molecular level. The results from this study could help control complications in cystic fibrosis and hospital infections due to contaminated equipment.
I have sat on this long enough. It’s not like a have anything else going on right now (except the birth of a son in a month, syllabus to write, classes to prepare, evaluations to do, data to journal, …). Introducing:
Here are the details presently. I and anyone willing to help will scour the journals of our respective fields and choose those we feel need to be disseminated to the larger public. In a short synopsis (abstract if you will), an overview of the article and why it is important will be written and deposited here. Details will be worked out on how to submit the abstracts in the near future.
Now is the time to act (or later if now is not convenient)!
The following link is profound. The current issue of EdgeScience takes a brilliant look at how the current era in science is more about rushing technology to market to benefit society than the underlying universal truths that must first be studied. The consequences have been strikingly similar to the ‘Housing Bubble’ and may not have fully burst yet.
I was recently approached about developing a children’s book to educate about bacteria in hopes of clarifying misconceptions many have about ‘nasty germs’. I must say how amazed and honored by the invitation I am. The company is small without a lot of capital to produce such a book at will. So, I was asked if I had contacts that would graciously sponsor the production of the book. This to me is bittersweet. I would love to be a part of something that would be so helpful for the public regarding the reality of microbes (they tend to get bad press in general). However, I’m not one to ask for money…ever.
This has sparked questions in my head about the state of educational media production. S.T.E.M. is all the rage these days and rightly so. As our society progresses, the need for a workforce trained for technical and scientific positions is essential. One example…billboard signs. Growing up, I used to get excited and amazed when I saw a person putting up a new billboard sign. Taking the old one off, applying the new one in its place. However, now these signs are replaced by digital billboards. Who is going to change the billboard advertisement? Someone trained to tear down the old and glue the new one on? Someone with a background in electrical engineering? If there is a problem with the billboard, who will fix it? A carpenter or an engineer? This is just one example.
The STEM push is necessary and welcome in my opinion. However, a quite fitting phrase comes to mind: show me the money. We are throwing money into public school systems that are fueled by bureaucracy and inefficiency. Yet we still have to cut out box tops to support local schools and have several fundraisers a year for a new gym floor. Anyone see the irony?
Put the money where it can be useful. Put it in projects that will encourage our children to pursue a career that will promote curiosity and critical thinking. This has been my soapbox, today sponsored by the letters S, T, E, and M.
Many do not place ‘bacteria’ and ‘memory’ in the same sentence. Normal human perception does not connect the two concepts. However, Mother Nature seems to have a more profound perception. The past 50 years or so of scientific investigation has shown how our uniqueness as humans is actually commonplace across all forms of life on Earth. Case in point, how closely associated molecular memory is between bacteria and human.
Bacteria use adaptation to signals as memory
Swimming bacteria do not move randomly in their environment. This behavior would be futile and counterproductive. Instead, bacteria are constantly monitoring their environment in search of food and poisons. Moving towards the former and away from the latter. This observation was first published in the late 19th century. Bacteria, like the famous and infamous E. coli, use molecular antennae to receive these important ‘signals’ as the basis in the decision of which direction to swim. What if the bacteria find a great place to reside with lots of food but still need to receive signals to ensure they remain there? The antennae have sections that can be modified easily and reversibly. These modifications, in the form of methylation, alter the sensitivity of the antenna protein to subsequent signals. Methylation allows these antennae not to receive the number of absolute signals but relative signals. In other words, the antenna protein through fine-tuned methylation detects changes in the number of signals now versus some time in the past. This is the basis of molecular memory.
These antennae are proteins called methyl-accepting chemotaxis proteins, or MCPs. MCPs accept methyl groups from the essential cofactor S-adenosylmethionine (aka SAM or AdoMet). AdoMet is essential to both prokaryotes and eukaryotes like humans. The methyl groups are added by a protein called CheR (pronounced ‘key R’) which transfers the methyl from AdoMet to very specific amino acid side groups of glutamate. The process, called O-methylation adds the methyl group to the single-bonded oxygen on the carboxyl.
The length of a bacterium’s molecular memory is very short in comparison to how we perceive memory at only a few seconds. But, to bacteria it is long enough to successfully navigate the environment with similar precision when concentrations of food or poison vary (up to several orders of magnitude, or ~1000x).
Does the basis of molecular memory in humans mimic bacteria?
Eukaryotes, including humans, use a very similar mechanism in signal transduction to bacteria. Phosphorylation (transferring a phosphate group from ATP or GTP to a protein amino acid) is the basis of all signal transduction and cell regulation. Bacteria use histidine kinases and response regulators, as do plants to some degree. However, the majority of regulation through signal transduction in eukaryotes is through two types of proteins, RAS proteins and the heterotrimeric G-proteins. G-proteins interact with membrane receptors that regulate their activity. What determines which surface receptors G-proteins interact with? Isoprenylcysteine methyltransferase, or ICMT, is one of two methyltransferases that regulate signal transduction activity. ICMT is a membrane protein that uses AdoMet to add methyl groups to isoprenylcysteine, a post-translationally modified cysteine residue on both heterotrimeric and RAS-related G proteins. Methylation regulates which receptors the G-proteins interact with, thus playing a major role in connecting the initial signal to downstream regulatory pathways. The carboxyl methylation essentially modulates G-protein signalling globally.
G-protein carboxyl methylation is regulated by GPCR signaling and, as seen above, GPCR signaling is regulated by G-protein carboxyl methylation. This feedback/feed forward loop could be seen as a form of molecular memory stored in methylation patterns. Within the brain, ICMT activity is almost exclusively found in the region controlling coordination of movement. Thus, methylation could be used to modulate certain neuronal signaling pathways which result in learned patterns of sensory-motor skills.
The only other major methyltransferase is from a protein known as PPMT. PPMT interacts with a major enzyme in signal termination, the protein phosphatase PP2A. PPMT adds methyl groups to the backbone carboxyl of a specific leucine in PP2A. This carboxyl methylation helps determine which B subunit PP2A interacts with and where in the cell PP2A can be found. PPMT structurally resembles CheR in bacterial memory. Moreover, the enzyme that removes the methyl group from PP2A, PME, structurally resembles the bacterial enzyme that removes methyls from MCPs, CheB.
PP2A is one of the major regulators of pathway coordination to maintain synaptic plasticity in the brain. Interestingly, methylation defects and PP2A-PME complexes are suggested to play a role in the cause of Alzheimer’s Disease and memory loss. Methylation defects leading to defective phosphatase activity of PP2A leads to accumulation of a phosphorylated subunit of the structural protein microtubule. In this phosphorylated form, the filaments used to keep axons structurally sound collapse and lead to loss of normal synapses. Therefore, molecular memory in the form of methylation plays a vital role in promoting normal brain activity and its disruption can ultimately lead to dementia.
Chicken, meet egg. Egg, meet chicken.
So, from bacteria to human, carboxyl methylation is necessary for memory. Did these pathways evolve individually in parallel, or did the memory we have today originate in the predominant lifeforms found within us?
Li and Stock. (2009) Biol. Chem. 390: 1067-1096. DOI 10.1515/BC.2009.133