Thematic Minireview Series on Antibacterial Natural Products: New Tricks for Old Dogs

Introduction

Not only have antibacterial natural products been an important source of life-saving medicines in the 20th century, but they also have played a pivotal role in the growth of biological chemistry as a discipline. In particular, polyketide and peptide natural products have been extremely rich sources of antibacterial agents that modulate essential microbiological functions, such as nucleic acid and protein biosynthesis, or the integrity of the cell envelope. Using four examples from these two antibiotic superfamilies, this thematic minireview series illustrates how natural products are continuing to present fundamental and translational challenges at the chemistry-biology interface. The choice of molecules is based on a common theme; in each case, important recent discoveries have set the stage for a deeper understanding of general principles associated with antibiotic biosynthesis and modes of action.

Two decades ago, genetic analysis of the biosynthesis of several prototypical polyketides and nonribosomal peptides revealed the existence of thiotemplate assembly mechanisms for the backbones of these antibiotics. These groundbreaking findings provided a foundation for three important themes in antibiotic biosynthetic research that have been fertile subjects of research since then. The first is the mechanistic similarity between thiotemplate megasynthases involved in antibiotic biosynthesis and their counterparts in fatty acid biosynthesis. In particular, whereas the reactions involving carrier proteins are well characterized by now, the molecular logic of these biosynthetic chaperones remains a mystery. A second set of questions pertains to the mechanisms by which polyketide synthases and nonribosomal peptide synthetases strike an enviable balance between tolerance and specificity. On one hand, specificity enables each megasynthase to synthesize a single antibiotic that presumably serves a strategic need for the producer microorganism. On the other, tolerance is necessary to allow these enzyme families to evolve rapidly, thereby yielding the breathtaking diversity of structurally complex natural products. Last but not least, the conceptual analogy between initiation, elongation, and termination of ribosomal protein biosynthesis has had a strong influence on mechanistic studies of non-template assembly line biosynthesis of nonribosomal peptides and polyketides. These themes are elaborated in the articles by Lars Robbel and Mohamed A. Marahiel on daptomycin, Lauren B. Pickens and Yi Tang on oxytetracycline, and David E. Cane on erythromycin.

Whereas non-template enzymatic assembly lines have been recognized as the predominant mechanism for peptide antibiotic biosynthesis in bacteria, some natural products, such as lantibiotics and thiopeptides, are ribosomally derived. Notwithstanding their ribosomal origins, they undergo extensive post-translational modifications to be converted into molecules endowed with atypical functional groups, rigid architectures, and proteolytic resistance. In their minireview on thiopeptides, Christopher T. Walsh, Michael G. Acker, and Albert A. Bowers discuss the remarkable story of biosynthesis of this class of antibacterial agents that has emerged within only the past few years.

The nexus between protein and antibiotic biosynthesis is multipronged. Three of the four antibiotic classes (tetracyclines, thiopeptides, and macrolides) discussed in the following minireviews are inhibitors of protein translation. (Acidic lipopeptides induce bacterial cell death by forming pores in the cell membrane.) Not coincidentally, protein synthesis itself has been the theme of a recent series of minireviews published in this Journal (1–4). The role of these natural products in elucidating the structure and function of the ribosome and its accessory proteins is widely recognized. What is less appreciated is the potential for harnessing oxytetracycline, erythromycin, or thiocillin biosynthesis to create new tools for probing the ribosome in the aftermath of recent structural biological breakthroughs. The corresponding minireviews address these possibilities. Similarly, as elaborated by Robbel and Marahiel, although the precise mode of action of daptomycin remains unknown, recent structural analysis also has led to a new model for calcium-dependent interaction between daptomycin and the bacterial membrane. For those interested in the chemistry and biology of antibiotics, the next decade promises to be an exciting and hopefully fruitful one.