Summer science

During the summer, scientific journals continue to publish papers. In this overview we highlight a number of summer papers from FSE staff.

How some bacteria escape antibiotics

Many microorganisms are adapted to a life of feasts and famines. They can lie dormant when food is scarce but will grow rapidly when it is available. However, there is a difference in how individual cells respond to a feast and this turns out to be important for the development of antibiotic tolerance. This discovery was made by microbiologists from ETH Zürich in Switzerland and from the University of Groningen.

In a paper that was published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).on 15 July, the scientists described a novel setup to study how starving bacterial cells respond to the appearance of food. Using this setup, they found that in populations of genetically identical bacteria there was huge variation in how individual cells responded to food: while many cells started growing exponentially, some did not respond to the abundance for a long time. Although the slow-growing cells contributed very little to the growth of the population, when the experiment was repeated in the presence of antibiotics, these cells did not die, whereas the rapid-growing ones did. Thus, having variation in response time appears to be useful as it allows a clonal population (in which cells are genetically identical) of bacteria to survive occasional antibiotic exposure, while still resuming growth rapidly after starvation. In other words, these bacteria are not putting all their eggs in the same basket.

Using an evolutionary model, the scientists confirmed this intuition and found that when there is fluctuating selection on rapid growth resumption after starvation and survival under stressful conditions (such as the presence of an antibiotic), bacterial populations evolve a wide range of lag times in responding to food. This strategy minimizes the cost of having slow-growing cells, as they help the population to balance the trade-off between growth and survival. These results show why bacterial populations can afford having cells that take a long time to resume growth and therefore the prevalence of antibiotic tolerance in the clinics.

Reference: Stefany Moreno-Gámez, Daniel J. Kiviet, Clément Vulin, Susan Schlegel, Kim Schlegel, G. Sander van Doorn, and Martin Ackermann: Wide lag time distributions break a trade-off between reproduction and survival in bacteria. PNAS, first online 15 July 2020.

New method to produce mimics of antibiotic peptides that are not gene-encoded

The central dogma of biology says that genetic information flows from DNA to RNA and subsequently from RNA to proteins. This means that to produce a protein or a peptide, you need a gene. However, this is not always the case. There is a range of non-ribosomally produced peptides, small proteins that are created by enzyme complexes (which are themselves gene-encoded), without the need for peptide-encoding DNA. Because of this, these peptides commonly contain amino acids that are not normally found in proteins.

Some well-known antibiotics, such as daptomycin, vancomycin and brevicidine are non-ribosomally produced peptides (NRPs). This has a major drawback: it is complicated to produce large numbers of variants of these peptides, for example to investigate resistance to antibiotics, as this is normally achieved by creating mutants of the original peptide using gene technology. Scientists from the University of Groningen presented a way around this problem. They created genes that produce peptides mimicking the NRP antibiotic.

This was not straightforward: brevicidine contains two amino acids that are not available in normal protein production. The team therefore replaced these with amino acids that have roughly the same chemical structure. Furthermore, they had to ensure that certain changes were made to the peptide following production, such as the formation of a ring structure and a mimic of a fatty acid tail.

In the paper that was published in the journal Cell Chemical Biology, they described how their synthetic gene produced peptides with similar antimicrobial effects as brevicidine. This means that by altering the gene, they can now quickly create a large number of variants and screen them for antimicrobial effects in a high-throughput system. They are confident that this technique can be used to make variants of other NRPs as well.

Reference: Xinghong Zhao, Zhibo Li, and Oscar P. Kuipers: Mimicry of a Non-ribosomally Produced Antimicrobial, Brevicidine, by Ribosomal Synthesis and Post-translational Modification. Cell Chemical Biology, first online 23 July 2020.

How knotting molecules changes the twist in liquid crystals

It is not just your earphones that get tangled into knots all the time. Long molecules such as proteins or DNA can also get tangled into knots. These knots are receiving an increasing amount of interest from scientists, who are curious to discover whether naturally occurring knots serve a purpose and how molecular knots tie themselves up.

In an article published in Nature Chemistry on 3 August, chemist Nathalie Katsonis and her team from the University of Groningen collaborated with David Leigh’s research group from the University of Manchester. Leigh is a supramolecular chemist, who has famously introduced essential concepts to achieve the synthesis of knotted molecules.

Their collaborative work features a ‘strand’, which is a linear molecule that is chiral - it is not superimposable onto its mirror image, comparable to a left and a right hand. In the presence of a lanthanide ion, this strand wraps itself around the ion and into a knot, with its own handedness that is opposite to that of the strand.

The researchers used liquid crystals as a matrix to investigate whether this inversion of handedness upon knotting could be translated into a macroscopic effect. The strand was added in very small amounts to a liquid crystal and a left-handed helix was formed. Forming the knot by adding the lanthanide ion lutetium changed the chirality of the liquid crystal into a right-handed helix. Thus, the molecular knot had a dramatic effect on a macroscopic scale.

This work shows how dynamic control over chirality can be achieved by inducing the formation of molecular knots. It also begs the question of whether such dynamic helical conversions, which are not uncommon in nature, could be the result of similar knotting in biomolecules.

Reference: Nathalie Katsonis, Federico Lancia, David A. Leigh, Lucian Pirvu, Alexander Ryabchun and Fredrik Schaufelberger: Knotting a molecular strand can invert macroscopic effects of chirality. Nature Chemistry 3 August 2020.

Stratingh’s Summer Streak

The Stratingh Institute for Chemistry at the University of Groningen had a remarkable summer: its scientists published no fewer than six papers in one or other journal from the Nature family – with two more in the pipeline. Even more remarkable is that the first three papers were all published on 26 June!

The first paper shows a practical application of molecular switches. To perform work in the visible world, you need a large number of these switches to work in unison. Chemists from the University of Groningen created a molecular network that contains molecular switches that can be flipped using ultraviolet light. Spheres from this material can take up gases, such as nitrogen or carbon dioxide, but as the switch is flipped, their capacity to store gas decreases. Such a system could be used to pick up gases and release them again.

Reference: Castiglioni, F., Danowski, W., Perego, J., Leung, F.K.-C., Sozzani, P., Bracco, S., Wezenberg, S.J., Comotti, A., Feringa, B.L.: Modulation of porosity in a solid material enabled by bulk photoisomerization of an overcrowded alkene. Nature Chemistry 26 June 2020.
See also: Molecular switches regulate gas adsorption on porous polymer

Life

The second and the third paper are both about something very closely resembling molecular life. In a system with self-replicating molecules – previously shown to have the capability to grow, divide and evolve – chemists from the University of Groningen have now discovered catalytic capabilities that result in a basic metabolism. Furthermore, they linked a light-sensitive dye to the molecules, which enabled them to use light energy to power growth. These findings from the Otto laboratory bring artificial life one step closer. Both papers featured in a Nature News article.

Reference: Jim Ottelé, Andreas S. Hussain, Clemens Mayer, Sijbren Otto: Chance Emergence of Catalytic Activity and Promiscuity in a Self-Replicator. Nature Catalysis 26 June 2020.
Guillermo Monreal Santiago, Kai Liu, Wesley R. Browne, Sijbren Otto: Emergence of light-driven protometabolism upon recruitment of a photocatalytic cofactor by a self-replicator. Nature Chemistry 26 June 2020.
See also: Life-emulating molecules show basic metabolism

Furthermore, Sijbren Otto and his colleagues wrote a review article on how chemical systems could acquire fundamental properties of life, such as growth and replication. This article was published on 1 July in Nature Reviews Chemistry.

Reference: Adamski, P., Eleveld, M., Sood, A., Kun, Á., Szilágyi, A., Czárán, T., Szathmáry, E., Otto, S. From self-replication to replicator systems en route to de novo life. Nature Reviews Chemistry 2020.

Catalysis and knots

And finally, on 13 July, the Ben Feringa group published a paper on a new catalytic system that allows a much more environmentally friendly synthesis of many drugs and other useful chemicals.

Reference: Helbert H., Visser P., Hermens J.G.H., Buter J., Feringa B.L. Palladium-Catalysed Cross-Coupling of Lithium Acetylides. Nature Catalysis 2020.

Finally, Nathalie Katsonis and colleagues from Manchester published a paper on molecular knots in Nature Chemistry on 3 August, as is reported above in the summer news.

Apart from these six published papers from the Stratingh Institute, two more have been been accepted for publication in Nature Reviews Chemistry and Nature Chemistry. So, the summer streak continues!