Current Topics in Medicinal Chemistry - Volume 3, Issue 9, 2003

A substantial number of antimicrobial agents target some activity of the bacterial ribosome for inhibition. Mechanistic studies and recent structural investigations of the ribosome have identified the binding sites and presumed mechanism of inhibitory activity for some compounds. A second target for many of these antibiotics has recently been examined. Formation of both 30S and 50S ribosomal subunits in bacterial cells is impaired by translational inhibitors. For many antimicrobial agents, inhibition of this target is equivalent to inhibition of translation in preventing cell growth. This review will describe features of this new target including the types of compounds which affect particle assembly and differences in the process in different microorganisms. The characteristics of this new target will be identified and aspects of a model to explain this new inhibitory activity will be explored.

Macrolides are among the most clinically important antibiotics. However, many aspects of macrolide action and resistance remain obscure. In this review we summarize the current knowledge, as well as unsolved questions, regarding the principles of macrolide binding to the large ribosomal subunit and the mechanism of drug action. Two mechanisms of macrolide resistance, inducible expression of Erm methyltransferase and peptidemediated resistance, appear to depend on specific interactions between the ribosome-bound macrolide molecule and the nascent peptide. The similarity between these mechanisms and their relation to the general mode of macrolide action is discussed and the discrepancies between currently available data are highlighted.

Clarithromycin and azithromycin, which are more acid-stable than erythromycin A (EM), have been widely prescribed for the treatment of respiratory tract infections because of their high efficacy and safety. However, these macrolide antibiotics are only weakly active against pathogens with an efflux gene (mef) and are inactive against pathogens with a methyltransferase-inducible gene (erm) and constitutively resistant organisms. To address the drug resistance issue, tremendous efforts have been devoted to the modification of the macrolide structure. As a consequence, several types of decladinosyl derivatives, such as ketolide and acylides, have been recognized to be effective against meftype resistant streptococci and methylase-inducible staphylococci. It has also been recognized that derivatives containing certain 11-, 6- or 4”-tethered aryl substituents, such as telithromycin (HMR 3647), cethromycin (ABT-773) and CP- 544372, are effective against erm(B)-type resistant streptococci. Telithromycin was recently approved in several European countries for the treatment of respiratory tract infections and cethromycin is now in the final stage of clinical study. Macrolide antibiotics have been modified to address the issues of acid-instability and inactivity against resistant strains. In this review, we will summarize the progress in the macrolide research area and discuss the desirable features of the next generation macrolide antibiotics.

Macrolide antibiotics exert antimicrobial effects by binding to the peptidyl transferase center of the 50S subunit of bacterial ribosomes and inhibiting protein synthesis. Hence, the structure of macrolides and their interaction with bacterial ribosomes have been investigated in order to understand the structural mechanisms of macrolide-ribosome interaction. Most macrolides have been found tom adopt a common conformation both in crystal form and in solution, which is believed to play an important role for binding to bacterial ribosomes as well as representing bi-facial property essential for excellent biological functions of macrolides. Chemical footprinting and mutant analysis have offered topological information on macrolide-ribosome interaction at the nucleotide level. Recently, crystal structures of the 50S ribosomal subunit and the 50S subunit with macrolide antibiotics have been published. These crystal structures provide much structural information on macrolideribosome interaction at the atomic level and will enable structure-based drug design of novel macrolide antibiotics with potent activity against resistant strains.

Protein synthesis is a central function in cellular physiology, and this important process is the target of many naturally occurring antibiotics and toxins. One such antibiotic is the aminoglycoside, which has been widely utilized in the clinical in the last fifty years due to their low cost and reliable activities. However the usage and applications of aminoglycosides have been severely limited due to their numerous side effects and resistance mechanism acquired by bacteria. Advances in understanding their mechanism of action have led to attempts in developing novel aminoglycoside-derivatives that would potentially eliminate harmful side effects and be resistant to aminoglycoside-modifying enzymes. This account provides a brief introduction to the various classes of antibiotics that target the ribosome, and also provide highlights in recent advancement of the synthesis of aminoglycoside analogs.

This review covers recent developments in several important aspects of research on oxazolidinone antibacterial agents. Structure-activity relationships are first discussed, emphasizing bioisosteric replacements for the both the oxazolidinone ring and the N-acetylaminomethyl group at C-5. The oxazolidinones have a mechanism of action that is distinct from other antibacterial agents, whereby protein synthesis is inhibited prior to initiation. Studies aimed at determining how the oxazolidinones bind to the bacterial ribosome and interfere with peptidyl transferase activity are described in detail, and are then related to the nature of the changes in the ribosomal RNA leading to resistance. Toxicity of the oxazolidinones remains a critical issue, in that early lead compounds exhibited lethal toxicity in animal studies. Preclinical and clinical safety studies of both eperezolid and linezolid are summarized, giving emphasis to histopathological effects observed in early animal studies. These studies are then related to thrombocytopenia and pancytopenia observed in patients treated with linezolid for extended time periods. Finally, studies to determine the nature and potential severity of drug-drug interactions in patients undergoing linezolid therapy are discussed.