Editorial [Chemical Evolution of Natural Product Antibiotics Guest Editor: Mark L. Nelson ]

As the problem of antibiotic resistance to the major families of compounds continues, so grows the efforts and complexity of chemically modifying natural product antibiotics to combat and thwart infectious disease pathogens, the topic of this issue of Current Medicinal Chemistry, Anti-Infective Agents. As chemical modification space disappears around simpler, more synthetically amenable families, such as the β-lactams and the quinolones, researchers around the world have developed synthetic and biological tools to study and synthesize more potent compounds with antibiotics of increasing chemical complexity and synthetic challenge. The goals of such endeavors are straightforward- to derive more potent antibiotics while deriving structure-activity relationships, particularly against antibiotic resistant organisms, while describing their mechanisms of biological action. The contributors to this issue represent current scientific fronts in this area, the chemical modifications of complex antibiotics and insights into their biochemical mechanisms, in families of antibiotics that are progressing to their full therapeutic potential. The first scientific front of considerable interest, based upon the peptide antibiotic superfamily and the approval of daptomycin (Cubicin®) for clinical use against Gram-positive pathogens, is provided by Professor M. Marahiel and colleagues from Philipps-Universität, Marburg, detailing the latest efforts in the chemoenzymatic modification of non-ribosomally synthesized proteins. Such proteins have important commercial, therapeutic and biochemical uses, and the study of the biosynthetic pathways and further chemical modifications holds future promise in the areas of industrial synthesis as well as to produce the next generations of antibiotic agents. Lantibiotics, also active natural product peptides that are post-translationally modified, are a second scientific front that is studied worldwide and the subject of one of the leading research laboratories studying their chemistry and mechanisms of action, led by Professor Robert Kaptein at Utrecht University. The lantibiotics have structure-activity relationships directed to the Lipid-II complex, and both their chemical dynamics, studied by high-field NMR, and biochemical mechanisms are detailed here. Such detailed mechanisms may also serve for the future design and therapeutic implementation of this important family of related antibiotics. The aminoglycosides are an extremely important family of related antibiotics, and are composed of both simple derivatives and more complex compounds, capable of inhibiting the growth of a broad spectrum of bacteria. More importantly, specific aminoglycosides have potent activity against the Gram-negative bacteria, and are used therapeutically for their treatment. However, there are few new derivatives or novel structures that have made it to the clinic, although the scientific front concerning new chemistries applied is considerable. Professor Chang and his colleagues from Utah State University are on the fore-front of such research, and show in detail the efforts worldwide to synthesize or semisynthesize new aminoglycoside derivatives. Carbohydrate chemistry is an extremely complex subject yet will be rewarding, provided that newer derivatives can be used against problematic pathogens, primarily residing with the Gram-negative subset of bacteria. In the future, antibiotics will be more complex, as bacteria become more defensive. The articles herein will hopefully act as the first line in developing more potent and useful compounds, as both compounds and bacteria evolve.