Resistente Bakterien sind für die Antibiotikaforschung eine echte Herausforderung. In München konzentrierte man sich auf Antibiotika, die ihre Wirkung in den Ribosomen entfalten sollen.
Current trends indicate that microbes have the upper hand in our ongoing struggle against bacterial infections. Firstly, there is an increasing prevalence of “superbugs” within the public health sector that have resistance to more than one drug; recent outbreaks of the enterohaemorrhagic E. coli (EHEC) were detected in Germany in 2011, and the New Delhi metallo-beta-lactamase-1 (NDM-1) strains appeared in the UK and Europe in 2010.
Secondly, our arsenal for retaliation is limited by the lack of new classes of antibiotics entering into clinical practice - only three truly new classes of antibiotics have entered into clinical practice within the past 30 years. Moreover, the problem is compounded by the exodus of large pharmaceutical companies from the research and development of novel antimicrobial agents - an exodus at a time when our need is most dire. This leaves the burden of discovery of new antimicrobials as well as investigations into the mechanism of action of antibiotics predominantly in the hands of small biotech companies and academics, such as my research group.
Stopping the Megalithic Machine
The term “antibiotic” comes from the Greek anti (against) and bios (life), and refers to the ability of small compounds (typically <1,000 Daltons, a unit of atomic mass) produced by one species of bacteria (or fungus) to kill or slow the growth of another. While antibiotics target a variety of different fundamental processes in the cell, ranging from DNA/RNA replication to cell wall biogenesis, my group focuses specifically on the large and diverse group of antibiotics that target the ribosome, a large (~2,500,000 Daltons) factory in the cell that synthesizes protein.
The research team is interested in how small molecules, like drugs, can stop a large megalithic machine, like the ribosome, in its tracks - a feat reminiscent of the David versus Goliath story. To address this question, the Wilson group applies structural and biochemical approaches to investigate the mode of interaction that different classes of antibiotics have with the ribosome.
The structural approach involves visualizing antibiotics bound to the ribosome using X-ray crystallography. The ability to elucidate the interactions between the antibiotic and its binding site on the ribosome is extremely beneficial for the development of novel antibiotic derivatives. One such study involving the Wilson group has revealed how the “last-resort” antibiotic linezolid binds within the active site of the large ribosomal subunit.
The identification of the regions of the drug that are important for interaction with the ribosome, as well as those that are not, provides drug designers with potential sites for modification - that is, it gives the designers the ability to attach chemical moieties to specific sites to enhance pharmacokinetic properties or establish additional interactions of the drug with the ribosome. Establishing a stronger interaction between the drug and the ribosome can lead to improved antibiotics that overcome certain ribosome-related resistance mechanisms.
Overcoming the Mechanisms of Resistance
Unfortunately, many of the naturally produced antibiotics, suchas tetracycline, erythromycin and chloramphenicol, have become ineffective due to acquired resistance of pathogenic bacteria and therefore cannot be used clinically. “Bacteria are extremely clever at developing novel ways to obtain resistance to antibiotics”, says Agata Starosta, a PhD student in the my laboratory. Common mechanisms of antibiotic resistance include efflux pumps that remove the drug from the cell and alterations of the drug target, or of the drug itself, so as to prevent a drug-target interaction.
During her PhD studies, Agata has developed a number of assays to screen antibiotics for their ability to overcome ribosome-related resistant mechanisms. In particular, Agata can demonstrate the effectiveness that third generation tetracyclines, such as tigecycline, have against common tetracycline-resistance mechanisms. “Tigecycline not only overcomes efflux pump resistance mechanisms but also binds more strongly to the ribosome, making it a much more effective protein synthesis inhibitor”. Semi-synthetic derivatives of natural antibiotics have been successfully deployed as part of our “counterattack” against multidrug-resistant bacteria.
Most clinically used antibiotics target a relatively limited number of sites on the ribosome and therefore cross-resistance between different antibiotic classes is common. There do exist, however, naturally produced antibiotics, such as the orthosomycins (evernimicin) and thiopeptides (thiostrepton and micrococcin), which target distinct sites on the ribosome. Development of these compounds for clinical usage will definitely provide a boost to our future drug arsenal.
We must better understand the mechanism by which these antibiotics inhibit protein synthesis, which in turn requires that we understand the fundamental process of protein synthesis. Thus, to keep one step ahead of the microbes, it will be necessary to invest not only in drug development per se, but also in the basic research that provides the foundation for our knowledge.
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