Hunger for antibiotics

Many antibiotics are produced by the family of bacteria known as Streptomyces. A team of biochemists has unraveled the mechanism which causes streptomycetes to produce antibiotics. And they discovered that streptomycetes can be encouraged to make other types of antibiotics. This is an important discovery as dangerous pathogens are increasingly developing resistance to commonly used antibiotics.
The team comprises researchers from the universities of Leuven (Dr Sébastien Rigali), Erlangen (Dr Fritz Titgemeyer) and Leiden (Dr Gilles van Wezel). The research is primarily being conducted by post-doc Rigalo in Van Wezel’s laboratory at the Leiden Institute of Chemistry (LIC). They report on their research in the cover story of the July edition of EMBO reports of the European Molecular Biology Organization. The article is featured as Research Highlight in the August edition of Nature Reviews Microbiology.
Musty smell
Streptomycetes are bacteria, but in their lifestyle they are more like filiform fungi. In the soil they form a filamentous network, a so-called mycelium. They are responsible for the typical musty forest smell. As the nutrients in the soil become exhausted, aerial filaments are created – with fungi and mushrooms – to form the spores which enable them to spread.
The team chose as the object of its research Streptomyces coelicolor – the model system for the study of bacterial development and antibiotic production, since the sixties intensively studied by co-author Sir David Hopwood. The nutrients on which this genus grows comprises two main elements: chitine – a natural polymer from which the exoskeleton of insects is formed – and N-acetylglucosamine – a carbohydrate from which the bacterial cell wall is also made. When the food supply becomes exhausted, the streptomycete wants to become airborne in order to reproduce. It needs nutrients in order to be able to do this. Because it is no longer able to obtain these nutrients from the soil, it decomposes its underground mycelium and consumes its own cell walls.
In the soil there are millions of other bacteria which also lack nutrients. As the streptomycete decomposes in order to make nutrients, it attracts other bacteria. As streptomycetes grow slowly, they run the risk of becoming overrun. Streptomycetes and fungi produce antibiotics to ward off these bacteria attacks. And we humans gratefully make use of this characteristic to cure bacterial infections.
‘We had already discovered that the streptomycete contains a protein, known as DasR,’ explains Van Wezel. ‘DasR is a regulatory protein that can switch many genes on and off, thus controlling the development of the streptomycete. And we also knew that DasR is involved in recognising nutrients.’ While there are sufficient nutrients – particularly chitine – the protein prevents the formation of aerial mycelium, spores and antibiotics. Van Wezel: ‘If the streptomycete takes chitine from the environment, there is a state of abundance, but if it starts to consume its own cell walls, there is a state of poverty and something has to be done about it.’ He compares it to the role of Cerberus, the guard dog at the gate of Hades, the guard from Greek mythology. ‘Just as Cerberus prevents the dead souls from crossing the Styx and returning to the world of the living, DasR restrains the genes which cause spores to be formed. And, a very important point, it also blocks the production of antibiotics.’
The researchers discovered that N-acetylglucosamine plays a significant role in the whole cycle. ‘Rigali demonstrated that if you add N-acetylglucosamine to the nutrient, the streptomycete suddenly starts to produce large quantities of antiobiotics,’ says Van Wezel. ‘And also antiobiotics which we do not see normally. Apart from the three or four clusters which were already known, there are about twenty more hidden on the genome. Some clusters are controlled only by DasR, whilst others are only minimally influenced by this protein. These are the clusters which are always visible. Probably because under natural circumstances concentrations are not achieved which would switch off DasR completely, the suppression system remains switched on. If you add a lot of N-acetylglucosamine, all the DasR is switched off and the clusters are switched on.’ To continue the comparison with Cerberus: N-acetylglucosamine is in other words the bone that is thrown to DasR to keep it quiet, so that the streptomycete can cross from the underworld to the world above.

(22 July 2008/SH)



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