A novel method to biosynthesize fluorinated antibiotics has the potential to revolutionize antibiotic drug development.
A German-US coalition of researchers from Goethe University Frankfurt (Germany) and the University of Michigan (MI, USA) have added a new element to the production of an antibiotic, erythromycin, to create novel analogues to combat increasing resistance.
Fluorinated molecules are almost ubiquitous in medicinal chemistry. In fact, nearly half of all small-molecule drugs approved by the Food and Drug Administration contain at least one fluorine atom.
Fluorine, the first halogen, has several physiochemical properties that make it an ideal candidate for a constituent on a drug molecule. A carbon–fluorine bond is considerably harder to break than a carbon–hydrogen bond; this is due to fluorine’s almost insatiable thirst for electrons. Additionally, a carbon–fluorine bond is exceptionally non-polar, offering little attraction to aqueous molecules. This means that its solubility in water is decreased; however, its lipophilicity, or its solubility in fat, is increased. Consequently, this increases the bioavailability of a fluorinated molecule when compared to a non-fluorinated molecule.
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While fluorination is common in medicinal chemistry, it is seldom seen in nature. Fluorinating organic molecules is notoriously difficult and often hazardous. A running joke amongst chemists is that it is easy to spot a fluorine chemist – all you have to do is count their fingers. High temperatures, dirty processes and heavy metal catalysis are often required to add this valuable element to molecules, and the selectivity of where you can substitute a fluorine atom is also very limited. A greener, cleaner and simpler method is needed to introduce fluorine to pharmaceuticals.
Polyketide synthesis is a commonplace biosynthetic phenomenon and very useful to the medicinal chemist. Antibiotics, cancer therapeutics and other valuable medicines can be produced via this natural pathway. The process is catalyzed by a series of enzymes known as polyketide synthases, which can be seen as an assembly line in a factory; distinct units arranged sequentially and each performing a unique function. In this study, the team focused on the biosynthesis of erythromycin, an antibiotic, as a starting point.
Erythromycin is commonly prescribed in humans and animals for several bacterial infections. Consequently, bacteria have developed resistance mechanisms against the antibiotic. The team hypothesized that creating fluorinated derivatives of erythromycin may create novel candidate drugs with the ability to overcome antibiotic resistance. Moreover, it would open the door for other fluorinated polyketide drugs.
To do this, they added a new step on the polyketide synthase production line. Using strategic gene editing, the team successfully integrated a subunit from the murine fatty acid synthase (FAS) pathway. FAS is responsible for the production of fats and fatty acids in mice. FAS pathways are also readily exploited by biochemists as their end products are tuneable for one key reason: they are remarkably unselective when it comes to starting materials. Adding this FAS subunit into the bacterial polyketide synthase pathway allowed the incorporation of fluorinated molecules into synthesis of polyketides at strategic locations.
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The team are optimistic about this new metabolic engineering process and feel it has the potential to revolutionize polyketide drugs: “There are about 10,000 known polyketides, many of which are used as natural medicines,” explained lead author Martin Grininger (Goethe University, Germany). “Our new method thus possesses a huge potential for the chemical optimization of this group of natural substances – in antibiotics primarily to overcome antibiotic resistance.”
Work is ongoing to test fluorinated compounds for antimicrobial activity as well as the development of new fluorine motifs for further optimization in tandem with David Sherman (University of Michigan) and his lab. Co-author Alexander Rittner (Goethe University, Germany) has founded a start-up, kez.biosolutions GmbH, to further pursue these new fluorinated antibiotics.
However, the team stress the need for a public–private partnership between academia and industry. Co-author Mirko Jappe (Goethe University, Germany) noted, “Research on antibiotics is not economically lucrative for various reasons. It is therefore the task of the universities to close this gap by developing new antibiotics in cooperation with pharmaceutical companies.” Jappe went further to explain the relevancy of the new technique, “Our technology can be used to generate new antibiotics simply and quickly and now offers ideal contact points for projects with industrial partners.”
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