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Abstract
The emergence of pathogenic bacteria resistant to virtually all available antibacterial agents at present has caused consternation among medical professionals, but has only intermittently raised concern among the public. This has led to a transient resurgence of interest in studying the mechanisms of resistance and in discovering and developing new antibacterial agents, but successes in the development of novel antibacterial agents have been few and far between. Although it has been known since the discovery of the tetracyclines that they are inhibitors of protein synthesis, there has been considerable recent progress on elucidating the mechanisms of action of the tetracyclines and in the enhanced understanding of the mechanisms of tetracycline resistance. In this case study, the authors discuss the discovery and development of a new class of antibacterials, which were derived from the tetracyclines, namely the glycylcyclines. This has resulted in the introduction of a new agent, tigecycline, to clinical practice. The glycylcyclines restore the antibacterial activity to levels of the earlier tetracyclines when they were first introduced, by overcoming the two major tetracycline-resistance mechanisms of efflux and ribosome protection, which promises to have a high degree of clinical utility.