The use of the element fluorine to modify active substances is an important tool in modern drug development. Active drug agents have been chemically modified with fluorine for decades, owing to its numerous therapeutic effects: Fluorine can strengthen the bonding of the active agent to the target molecule, make it more accessible to the body, and altering the time it spends in the body. Bacteria and fungi often manufacture complex natural compounds to obtain a growth advantage. One possible route for the development of drugs from natural compounds is to modify these substances by adding one or more fluorine atoms. However, the synthetic-chemical methods for inserting fluorine into natural substances are very complicated. Owing to the chemical and reaction conditions that are necessary, these methods are frequently “brutal”; this means, for example, that chemists are very limited in selecting the positions where the fluorine atom can be attached.
Nearly half of the small-molecule drugs currently approved by the U.S. FDA contain at least one chemically bound fluorine atom. These include cholesterol-lowering agents, antidepressants, anticancer agents and antibiotics. Chemists therefore are in serach for more practical, efficient and “green” options to performe this operation. There are rare cases of natural products produced by terrestrial organisms that contain fluorine atoms, but there are few cases and they represent very particular and interesting compounds used to understand cellular phenomena. Nevertheless, a much larger source of fluorinated compounds is marine biology: since the early 1990s biologists and chemists have been interested in the discovery of substances produced by organisms living in the oceans. Today at least 20,000 compounds of all sorts are known, and with distinct biological properties, produced by animals, corals, molluscs, fish, sponges and bacteria that live in the world’s seas.
A team at Goethe University Frankfurt has now achieved an important “first” by successfully fluorinating a natural antibiotic via targeted bioengineering of an antibiotic-producing bacteria. In this process, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of a macrolide antibiotic. With this method, an entire substance class of medically relevant natural products can be modified. The method has enormous potential for the manufacture of new antibiotic derivatives of erythromycin against resistant bacterial pathogens. Erythromycin is one of the representative of a gigantic substance class, the so-called macrolides or polyketides. There are about 10,000 known polyketides produced by living organimsms, many of which are used as natural medicines, for example as antibiotics, immunosuppressives or cancer drugs. Erythromycin works by binding to and blocking the activity of the bacterial ribosome, which is essential for bacteria to synthezie proteins.
Some bacteria have evolved ways to prevent this binding, making them resistant to treatment with antibiotics. Altering the antibiotic’s structure with a fluorine atom overcomes that evolutionary advantage, restoring the compound’s ability to fight bacteria. While chemists have developed methods for adding the fluorine synthetically, the process is arduous and requires the use of toxic chemical reagents. The new biosynthetic method overcomes those challenges, by inserting a subunit of an enzyme called fatty acid synthase into the bacterial protein. The enzyme is naturally involved in the biosynthesis of fats and fatty acids in mice. The fatty acid synthase is not very selective in processing the precursors, which are also important for the manufacture of antibiotics in bacteria. With this intelligent product design, the team succeeded in integrating the two processes. The added fluorine atom not only stabilizes the antibiotic, enhances the ability to kill bacteria and work safely in patients.
The search for drugs that overcome bacteria resistance is in continuous evolution: bacteria are under the constant evolutive pressure induced by new molecules for new mechanisms. It is, nonetheless, is a long-term task: depending on how frequently antibiotic are used, all these molecules will naturally cause sooner or later resistances.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Sirirungruang S et al. Nat Chem Biol. 2022; 18(8):886.
Rittner A, Joppe M et al. Nature Chem. 2022 Jul 25.
Thamban CN et al. ChemMedChem. 2021;16(1):124.
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Yu X, Zhang M et al. Eur J Med Chem. 2017; 125:515.
Beedie SL et al. Mol Cancer Ther. 2015; 14(10):2228.
Cabrita MT et al. Marine Drugs 2010 Aug; 8(8):2301-17.
Filler R, Saha R. Future Med Chem. 2009; 1(5):777-91.
Dott. Gianfrancesco Cormaci
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