New biosynthetic method for the production of antibiotics

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Drug-active agents have been chemically modified with fluoride for decades, due to its many therapeutic effects: fluoride can enhance the binding of the active agent to the target molecule, make it more accessible to the body, and modify the time spent in the body. . Nearly half of small molecule drugs (molecules up to about 100 atoms) currently approved by the US Food and Drug Administration (FDA) contain at least one chemically bonded fluorine atom. These include drugs as different as cholesterol-lowering agents, antidepressants, anti-cancer agents, and antibiotics.

Bacteria and fungi often manufacture complex natural compounds to gain 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. In the case of the antibiotic erythromycin, for example, the attached fluorine atom confers significant advantages. The new erythromycin produced by this process is more easily accessible by the body and more effective against pathogenic microorganisms that have developed resistance to this antibiotic. However, synthetic chemical methods for inserting fluorine into natural substances are very complicated. Due to the necessary chemical and reaction conditions, these methods are often “rough”, explains Martin Grininger, professor of organic chemistry and chemical biology at Goethe University. “This means, for example, that we are very limited in selecting the positions where the fluorine atom can be attached,” he adds.

A German-American scientific team led by Professor Martin Grininger and Professor David Sherman, professor of chemistry at the University of Michigan, has now succeeded in using the biosynthesis of an antibiotic-producing bacterium. In this process, the fluorine atom is incorporated as part of a small substrate during the biological synthesis of a macrolide antibiotic. “We are introducing the fluorine unit during the natural manufacturing process, an approach that is both efficient and elegant,” Grininger points out, “This gives us great flexibility when positioning the fluorine in the natural substance – and allows us to influence its efficiency.”

To this end, project leaders Dr Alexander Rittner and Dr Mirko Joppe – both members of Grininger’s Frankfurt research group – inserted a subunit of an enzyme called fatty acid synthase into the protein. bacterial. The enzyme is naturally involved in the biosynthesis of fats and fatty acids in mice. Fatty acid synthase isn’t very selective in processing precursors, which are also important for making antibiotics in bacteria, Rittner says. Through clever product design, the team succeeded in integrating a subunit of the murine enzyme into the corresponding biosynthetic process for the antibiotic. “What is exciting is that with erythromycin we were able to fluoridate a representative of a gigantic class of substances, the so-called polyketides,” says Rittner. “There are around 10,000 known polyketides, many of which are used as natural medicines, for example as antibiotics, immunosuppressants or anti-cancer drugs. Our new method therefore has enormous potential for the chemical optimization of this group of natural substances – in antibiotics primarily to overcome antibiotic resistance.” To exploit this potential, Dr. Alexander Rittner founded the startup kez.biosolutions GmbH.

Prof. Martin Grininger has been conducting research on the tailor-made biosynthesis of polyketides for several years. “Our success in the fluoridation of macrolide antibiotics is a breakthrough that we worked hard for and that I am now very proud of,” he says. “This success is also a boost for the future. We are already testing the antibiotic effect of various erythromycin fluorinated compounds and additional fluorinated polyketides. We intend to expand this new technology to include fluorinated motifs additional studies in collaboration with Professor David Sherman and his team at the University of Michigan in the United States.

The search for drugs that overcome antibiotic resistance is a long-term task: depending on the frequency of use, all antibiotics naturally cause resistance sooner or later. In this context, Dr. Mirko Joppe also believes that his work has wider implications for society. “Antibiotic research is not economically lucrative for various reasons. It is therefore the task of universities to fill this gap by developing new antibiotics in cooperation with pharmaceutical companies,” he explains. “Our technology makes it simple and fast to generate new antibiotics and now offers ideal touchpoints for projects with industrial partners.”

The polyketide research described above was supported by the Volkswagen Foundation (as part of a Lichtenberg Chair), the LOEWE MegaSyn research initiative funded by the Hessian Ministry of Science and Arts and the National Institute of Health in the United States.

Reference: Rittner A, Joppe M, Schmidt JJ, et al. Chemoenzymatic synthesis of fluorinated polyketides. Nat Chem. 2022. do: 10.1038/s41557-022-00996-z

This article was republished from the following materials. Note: Material may have been edited for length and content. For more information, please contact the quoted source.

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