Can we teach microorganisms to produce more efficient antibiotics? The molecular Lego is the key
Malaria, streptococcal and staphylococcal infections Microorganisms causing diseases are becoming more resistant to existing antibiotics, according to a February report by the World Health Organization. Over the last 30 years, no new group of antibiotics has been released. We have not heard of more effective active ingredients in existing antibiotics either. However, microbiologists from the BIOCEV research centre have succeeded. News about their discovery caught the attention of the professional public and was featured on the cover page of the May issue of the prestigious Chemical Science. No other Czech team has been this successful.
The original recipe for new antibiotics was inspired by “molecular Lego” – a modular principle used by microorganisms to build natural substances. “The new antibiotics called CELIN and ODCELIN combine CELesticetin and LINcomycin, two natural lincosamides that have been known since the 1960s. All efforts to obtain more effective lincosamide antibiotics have been logically centred on the chemical treatment of limcomycin, which is the more effective of the two. This gave rise to the most frequent medication from the group, clindamycin,” explains Jiří Janata, the Head of the Structure and Functions of Natural Substance Laboratory (the Institute of Microbiology of the Czech Academy of Sciences within BIOCEV). “No one had ever thought about combining lincomycin with less active celesticetin. From the chemical perspective, it is very complicated and researchers did not have the required knowledge for centuries,” adds Janata. Researchers even believe that they can programme microorganisms so that they directly produce new medications. They are planning to combine genes for lincomycin and celesticetin into one production organism.
Janata’s team has been studying how natural lincosamides are formed in microorganisms for more than 10 years. Understanding these complicated processes has enabled researchers to find the right combination of natural building rocks and create new antibiotics without chemical processes. “Through this step, we have imitated, or even got ahead of nature, where the evolution of natural antibiotics actually happens in a similar way. We believe that the new substances that we have prepared exist in nature, but have not yet been discovered,” says Zdeněk Kameník, one of the authors of the successful article. The researchers themselves were surprised by the multiple antibiotic effects compared to industrially manufactured lincomycin. They have patented the new substances and have begun extensive testing of their effects on a wider group of microorganisms, including those that are resistant to existing antibiotics. They have prepared more than one hundred other substances in this manner. Some of them are expected to be highly effective against malaria. However, for commercial purposes, it will be decisive whether the researchers can prepare microorganisms that directly produce such substances. Even if the development is successful, there are still many years of work to be done before any medication can be administered to patients.
“Resistance to antibiotics is nothing new. It has existed for millions of years together with antibiotics. Last century, people outsmarted the microorganisms that had been causing fatal diseases until then. We started to apply substances from different environments, mostly from the soil. Thanks to that, we have extended human life many years. And we consider that a definite victory. However, that is no longer the case as pathogenic microorganisms have learned to resist to our antibiotics. If we want to defend our victory, we have to prepare ourselves for a permanent fight involving the development of new substances. The length of the process from basic research to applicable medication has been 20 to 30 years. We find ourselves approximately midway through the struggle,” says Janata.
Link to the publication: http://pubs.rsc.org/en/content/articlelanding/2017/sc/c6sc04235j#!divAbstract
Lincosamide antibiotics are used, among other things, in the treatment for staphylococcal and streptococcal infections as an alternative to penicillin, including against resistant strains. The natural substances are celesticetin and lincomycin. Lincomycin is used as an antibiotic in human and veterinary medicine and for the chemical preparation of clindamycin. Clindamycin is the most effective ingredient in the group today; in addition to its antibiotic properties, it inhibits certain parasites (such as Plasmodium and Toxoplasma) and in combination with other substances, it is sometimes used for the treatment of malaria.
The BIOCEV Centre is a joint project of two faculties of Charles University and six institutes of the Academy of Sciences of the Czech Republic. Today, approximately 400 researchers and students work in the Biotechnology and Biomedicine Centre. Almost one-third of them are foreigners. Their joint objective is to learn details about organisms at the molecular level that will be used in applied research and in the development of new therapeutic procedures. BIOCEV’s research teams have published more than 450 research outputs, including articles in prestigious international journals (such as the Cell, Molecular Cell, Nature Communication and Gastroenterology and others).
Original press release from BIOCEV available here.