Small molecules, big players

Attention has been on big molecules, with spotlight being turned on gene expression and protein functions. Small molecules have, however, been the "star" for the last few years for researchers at the Department of Biological Sciences. The team at the Small Molecule Biology Laboratory led by Assoc Prof Sanjay Swarup, has made headways in this direction, especially in the last three years. Assoc Prof Swarup explained that small molecules can have diverse roles - from metabolism to signalling. For example, the nutrients for building blocks come from small molecules. A better understanding of how they work through their metabolic pathways may perhaps give answers to many of our health problems or suggest ways to divert pathways to overproduce useful products.








The networks in our cells are related to each other, said Assoc Prof Swarup, and if anything goes wrong in one part of the network, distant parts of the network may be affected. For example, drugs taken to combat certain diseases, in order for them to work, would have to affect a particular pathway of a certain group of cells. This may in turn, upset pathways of other networks, causing side effects. In order to understand better how side effects occur, scientists need to delve into the mysteries of metabolic networks of small molecules. Once such mysteries are solved, clinicians can help predict the side effects of drugs and perhaps come out with ways and strategies in improving therapeutics. In fact, said Assoc Prof Swarup, two-thirds of his laboratory, are busy with "metabolomics" -- an emerging science involving the study of metabolites from multiple pathways at specific times and under specific conditions. It requires a multi-disciplinary approach overlapping biology, chemistry, mathematics and computer science.

While studying the role of small molecules in bacterial movement in 2003, they made a significant discovery. The microbes they were working on, Pseudomonas putida, were able to move rapidly through soil and sand by removing a particular gene. Its corresponding protein, which the team has named "MorA" (for motility regulator A) functions as a "molecular brake". Without these brakes, the microbes could move around more than three times faster. Previously, scientists have thought that bacteria swim around by developing movement apparatus called flagella at certain stages only. But now, the team has discovered that Pseudomonas is fully capable of forming such apparatus throughout their life span and it can be accomplished by removing MorA.

Most remarkably, their team discovered that MorA likely functions by altering levels of a novel class of small molecule messengers - cyclic-di-GMP - that belongs to the general class of cyclic nucleotide messengers such as cAMP and cGMP. Since cGMP has not been reported from bacteria, it seems that they use cyclic-di-GMP instead of cGMP as in higher organisms including humans. This discovery would have applications in improving the prowess of bacteria currently being used for environmental applications such as to degrade pollutants. Their study was published in Plant Physiology (2003). On the flip side, the same discovery can be used to slow down the movement of harmful bacteria such as in human pathogens.

Assoc Prof Swarup said that though what they observed happened in a plant microbe, the same concept may be applied to human microbes with some modifications. Bacteria devoid of MorA throughout their life span, form flagella and are hence hindered in their ability to "hold on" to surfaces and form biofilms. These structures ("biofilms") are the principle causes of biofouling that occurs in water treatment membranes or in humans on surfaces of surgical implants such as catheters and corneal lenses. In cystic fibrosis patients, Pseudomonas form a film that clogs the lungs. Removing the "molecular brakes" in these bacteria may make them move on instead of anchoring themselves to certain areas to form a layer, thereby preventing the formation of biofilms.

Videotapes and truths of small molecules

The team also has "concrete evidence" on what makes bacteria move. One important find is that through a series of sensing and signalling, the flagella (long filaments which help bacteria move) increase in concentration so that the bacteria can move to another food source. The team has managed to capture on their imaging systems, the movements of bacteria. Once they have gained a better understanding, they can target bacteria cells to alter their signals and move as and when required, said Assoc Prof Swarup.