Antibiotics cheaper to produce

By switching off a single gene, the bacteria Streptomyces coelicolor can produce up to six times as much antibiotic. This is revealed in research carried out by biologist Jeroen Siebring, who is graduating from the University of Groningen on 5 February 2010. Thanks to this fundamental new insight, it may well be possible to produce important strains of antibiotics more cheaply in the future.

Antibiotics are medicines that are used to combat bacteria in the body. They are of huge importance for treating many different ailments, from infected wounds to sexually transmitted diseases. Antibiotics are produced in the pharmaceutical industry using bacteria, among others. The strain Streptomyces is one of the most common of these.

Model bacteria

Streptomyces coelicor is an important research model for a large group of antibiotic-producing bacteria, the streptomycetes. One of the reasons that PhD candidate Jeroen Siebring used S. coelicolor for his own research was that it is the only streptomycete for which the entire genome has been sequenced. The research produced fundamental insights into the way in which streptomycetes convert glucose into antibiotics and the role that the phosphofructokinase (pfk) enzyme plays in this. Glucose is the chief energy source for bacteria and they use pfk to break down the sugar. However, while most bacteria produce only one type of pfk, the bacteria S. coelicolor produces three.

Different phases

Siebring investigated why S. coelicolor can use three pfks, among others by studying the bacteria’s life-cycle. It turns out that the pfks are active in different phases: where pfkA2 is active in almost all of the tested growth conditions and growth phases, pfkA1 and pfkA3 are only activated under specific conditions. The pfkA3  enzyme is active during the maximum growth phase; pfkA1 and pfkA3 join forces when the bacteria’s growth is inhibited by a limited supply of nutrients.

Shutting down gene production

By intervening in the bacteria’s genome, the production of the separate pfks can be stopped. Siebring shut down the genes responsible for producing the three pfks one by one. He discovered that if the production of pfkA1 and pfkA3 is stopped, the bacteria commences to produce one and a half to two times as much antibiotic. If the production of pfkA2 is halted, the bacteria can produce up to six times more antibiotic than usual. Shutting down the genes had no effect on the bacteria’s growth.

Ground breaking

Siebring then sought an explanation for the increased antibiotic production. He discovered that when the production of pfkA2 is halted, less glucose is broken down and converted into the molecule fructose-6-phosphate, so that this molecule begins to accumulate. The molecule is processed in a different metabolic chain, the ‘pentophosphate pathway’, and NADPH is produced, a substance that plays an important role in antibiotic production. This ground breaking research revealed for the first time that the three pfks each fulfil a different function in S. coelicolor. Further research will try to discover the genetic cause of the different functions.

Cheaper

The new fundamental insights into the way in which streptomycetes convert glucose into antibiotics, and the role of pfks, are not only interesting from a scientific point of view; they may also have a practical application. Because the genetical modification does not impede the growth of the bacteria, up to six times as much antibiotic can be produced from the same amount of nutrient base. This could lead to cheaper antibiotic production.

Curriculum vitae

Jeroen Siebring (Odoorn, 1979) studied Biology in Groningen. He carried out research with the Microbial Physiology research group and at the Groningen Biomolecular Sciences and Biotechnology Institute (GBB), both part of the Faculty of Mathematics and Natural Sciences of the University of Groningen. His PhD supervisors are Prof. L. Dijkhuizen and Dr G. van Keulen. Siebring will continue to work at the University of Groningen after he has received his PhD. The title of his PhD dissertation is ‘The phosphofructokinases of Streptomyces coelicolor’.

Contact

- Jeroen Siebring, tel. +31 (0)50–363 22 02, j.siebring rug.nl
- Prof. Lubbert Dijkhuizen