Using X-ray crystallography to combat drug-resistant pathogens

Even in the US, antibiotic-resistant infections kill more than 20,000 people each year. Through the use of X-ray crystallography, Dr. Yury Polikanov probes the nature of this resistance at the molecular level to derive new antibiotics less prone to manipulation. View Halo Profile >>

Tell us about your research?

Our research is focused on elucidating the structure and functions of the ribosome, understanding the basic principles of protein synthesis in bacteria, the modes of action of ribosome-targeting antibiotics, and mechanisms of drug resistance at a structural level. While the general process of protein synthesis is relatively well understood, several fundamental questions central to the ribosome structure, function and evolution remain obscure. Understanding these aspects of translation is greatly facilitated by the use of X-ray crystallography technique that provides a structural basis for the molecular mechanisms, by which the ribosome and associated translation factors (such as release factors) achieve their roles in protein synthesis.

Our research is focused on elucidating the structure and functions of the ribosome, understanding the basic principles of protein synthesis in bacteria, the modes of action of ribosome-targeting antibiotics, and mechanisms of drug resistance at a structural level.

We use cutting-edge X-ray crystallography technique to determine atomic-resolution structures of the bacterial ribosome in functional complexes with various translation factors and ribosome-targeting antibiotics. Our structures provide the basis for the understanding of how different elements of ribosome function together at the molecular level. Importantly, using the functionally relevant ribosome complexes, such as those that contain natural tRNA substrates, we produce principally new data, highly relevant to the actual mechanism of action of an antibiotic or a translation factor.

Importantly, using the functionally relevant ribosome complexes, such as those that contain natural tRNA substrates, we produce principally new data, highly relevant to the actual mechanism of action of an antibiotic or a translation factor.

Can you explain that to a non-scientist?

The ribosome is a complex molecular machine that is responsible for synthesizing proteins, which are the essential building blocks of all living organisms. It is by the action of these ribosomes that the blueprint of life encoded in the DNA is translated into proteins that control every aspect of a living organism at a chemical level. The process of protein synthesis is called translation because ribosome interprets the language of nucleotides in genes into the language of amino acids in the proteins. There are tens and thousands of proteins in our body performing important functions like an immune response to pathogens, regulation of heartbeat, monitoring blood glucose levels, allowing oxygen absorption in the lungs, and neurotransmission, which are all made by the ribosomes. Hence the process of “protein translation” performed by the ribosome is critical for sustaining life. The principles of ribosome organization and functioning are fundamentally similar between all living organisms, however, nearly 3 billion years of independent evolution made our ribosomes slightly different from the ones found in bacteria. 

The principles of ribosome organization and functioning are fundamentally similar between all living organisms, however, nearly 3 billion years of independent evolution made our ribosomes slightly different from the ones found in bacteria. 

Because of these differences, it is possible for some natural compounds – antibiotics – to selectively inhibit ribosomes of pathogenic microorganisms (bacteria), and thereby kill them, with no effect on us (humans). Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than 50% of all medicines used to treat infections in the clinic. However, quick development of resistance to the existing antibiotics by pathogenic microorganisms demands a constant search for new antibiotics and represents a major health care threat in the United States and across the globe.

Quick development of resistance to the existing antibiotics by pathogenic microorganisms demands a constant search for new antibiotics and represents a major health care threat in the United States and across the globe.

It has been the long-term scientific focus of many laboratories to tackle this recurring problem and the Ribosome Structural Studies are at the forefront of addressing this very issue.

How could it someday impact patient lives?

Our vision is that our research will facilitate the development of next-generation antimicrobial compounds, as well as clinical approaches to prevent the acquisition of drug resistance by clinical pathogens.