INSTITUTE OF MICROBIOLOGY OF THE CZECH ACADEMY OF SCIENCES

LABORATORY FOR BIOLOGY OF SECONDARY METABOLISM

Head of laboratory: Ing. Jiří Janata CSc.

Microbial biosynthesis and metabolomics – Mgr. Zdeněk Kameník, PhD. (Krč)

Our team is interested in microbial specialized metabolites and their biosynthesis. A great number of these metabolites are biologically active and can be used eg. as antibiotics to treat bacterial infections, as antitumour compounds to fight cancer, or as immunity suppresors during transplantations. Our research focuses on non-pathogenic soil bacteria, actinomycetes, which represent a perfect source of bioactive natural metabolites. Specifically, we study the biosynthesis of lincosamide antibiotics such as clinically used lincomycin (its synthetic derivative is even an antimalarial). To get insight into the biosynthetic pathways, we use modern interdisciplinary approach from gene engeneering with CRISPR system up to advanced chemical analysis using mass spectrometry and nuclear magnetic resonance. Individual steps of the pathways are enabled through catalysis by biosynthetic enzymes. Interestingly, several enzymes involved in lincosamide formation are remarkable for their characteristics (unusual functions, cofactors, novel protein families, etc.). Examples of such enzymes that we currently described include F420H2-dependent reductases, deacetylases from the TldD/PmbA family, or a pyridoxal-5-phosphate-dependent lyase. Elucidation of the latter enzyme facilitated to combine two biosynthetic pathways and come up with a novel ´unnatural´ more effective lincosamide antibiotic named CELIN. This compound has been patented and we are conducting tests to assess the CELIN potential for clinical practice. Finally yet importantly, we investigate homologues of the remarkable lincosamide biosynthetic proteins including their metabolic pathways using untargetted mass spectrometry-based metabolomics. This approach leads to the discovery of novel compounds - we specifically aim to reveal new bioactive metabolites with a rare 4-alkyl-L-proline motif. Moreover, some of the studied enzymes likely play a role in primary metabolism and they may lead us to new therapeutic targets against pathogenic bacteria.

Antibiotic resistance group – Mgr. Gabriela Balíková Novotná, Ph.D. (Biocev)

Bacterial resistance is one of the biggest threats to global health. Reckless and excessive use of antibiotics in human and veterinary medicine or in agriculture have led to the emergence and spread of bacteria that are resistant to multiple antibiotics. Effective antibiotic treatment of multi-resistant bacteria such as MSRA - methicillin-resistant Staphylococcus aureus is becoming unavailable. It complicates successful therapies of much more serious health conditions such as cancer, transplantations or post-operative wound healings. We study the mechanisms of resistance against antibiotics. In other words, we are trying to figure out what makes an antibiotic against a given bacterium ineffective and how often it happens. Specifically, we focus on resistance to antibiotics targeting large subunit of bacterial ribosome (macrolides, lincosamides, streptogramins and pleuromutilins) and cell wall-targeting glycopeptides in gram-positive cocci. This knowledge is important to defeat resistant bacteria, either by choosing effective antibiotic to treat the infection or by developing new antibiotics that can overcome the resistance mechanism. However, bacterial resistance also has a positive role in nature. It allows soil bacteria to safely produce antibiotics without harming themselves and according to our most current ground-breaking research it can also play a role in regulation of the antibiotic biosynthesis. By understanding the mechanisms of antibiotic resistance and their regulation in environmental bacteria, we can better understand the natural role of antibiotics in bacterial communities. This knowledge will facilitate the search for new bioactive compounds which are often biosynthesized only in response to specific environmental stimuli.  

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