Evolutionary Inspirations For Drug Discovery

One of the most critical steps in drug discovery is the target identification. However, despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. The number of new drugs approved by Food and Drug Administration (FDA) has steadily declined over the past decade. In the meantime, the discovery and validation of novel targets continue to be low, and many targets and pathways have remained undruggable. It may be fair:to say that the recent decline in innovative drugs is largely due to exhaustion of validated and tractable targets. Owing to lack of new targets, the current approach for drug discovery is chemical modification of existing drugs. However, the emerging of resistance to newly approved drugs developed in this way can emerge in a rather short time (usually2-4years).To maintain a healthy pipeline of novel targets for drug discovery, conceptual innovations are needed to address the challenge of "more investments, fewer drugs" in the pharmaceutical industry. Evolutionary biology, as a basic science of medicine, can be helpful in the drug-discovery pipeline.By examining498successful human drug targets, it can be seen that approximately50%are associated with genetic disorders. Further analysis shows that these successfully targeted genes share some common evolutionary features. First, most of these genes (91%) have emerged before the bilaterian radiation, indicating genes appeared at early stages of life are relatively more druggable. Second, the therapeutic function of some successful targets is tightly linked to their evolutionary origins. For example, the majority of targeted genes evolved from metazoan are for cancer treatment while targeted genes evolved from eumetazoa are mainly for therapy of neurological diseases. These findings indicate that genetic disease genes are a rich source of human drug targets and evolutionary information can help identify drug targets with the greatest potential for therapeutic development.Several recent studies have revealed that the reactive oxygen species (ROS) induced by antibacterial stimulation can accelerate the evolution of antibiotic resistance. Considering many other mechanisms cause DNA mutations aside from ROS damage, evaluating the significance of oxidative DNA damage in the development of antibiotic resistance is of great interest. In this study, we examined the ratio of GC> TA transversion to GC> AT transition in drug-resistant Escherichia coli and Mycobacterium tuberculosis and found that ROS damage plays a critical role in the development of antibacterial resistance. Considering the long-term co-evolution between host organisms and pathogenic bacteria, we speculate that the hosts may have evolved strategies for combating antibiotic resistance by controlling DNA damage in bacteria. Analysis of the global transcriptional profiles of Staphylococcus aureus treated with berberine (derived from Berber is, a traditional antibacterial medicine) revealed that the transcription of DNA repair enzymes were markedly upregulated, whereas the antioxidant enzymes were significantly downregulated. This finding provides new clues for understanding how natural medicines prevent the evolution of antibiotic resistance and it has important medical implications for treating bacterial infections.