Multiple attack on bacteria by the new antibiotic teixobactin.

The international press acknowledges original research contributions from natural sciences only in rare cases. However, the story behind a recent publication in Nature about the discovery of teixobactin (1) experienced a worldwide euphoric echo in the media (“super-antibiotic”). How was this possible? In their contribution, Ling et al. not only reported on the discovery of a new lead structure that displays multiple modes of action, but also raised great hopes for the emergence of future antibiotics without the potential to develop resistance. In the search for new antibacterial leads against Grampositive pathogens, the appreciation of teixobactin as a new milestone is very plausible. Based on a collaboration between research groups from academia and the biotech industry, a sophisticated cultivation technology allowed the discovery of a new producing strain and a novel depsipeptide class (German Centre for Infection Research at the University of Bonn, Northeastern University Massachusetts, and NovoBiotic). A number of new drugs against problematic Grampositive bacteria (daptomycin, oritavancin, telavancin) have been approved in the past years. As a consequence, the research focus is currently shifting toward Gram-negative pathogens. Nevertheless, there remains a clear medical need for new compound classes with new mechanisms of action against Gram-positive bacteria. Still, it is questionable whether antibiotics without the risk of emerging resistances are a realistic scenario. Experience gained over decades teaches us that antibiotics generally encounter bacterial resistance, both because of false usage but also because of their correct use. The emergence of resistance is unavoidable! This statement was valid for drugs with a single mode of action, for example, rifampicin, as well as for those with multiple modes of action, for example, glycopeptides. Even if there is no experimental evidence for resistances against teixobactin, there is a high probability that resistance will kick in sooner or later. Indeed, resistances have been observed earlier than initially anticipated for nearly all classes of antibiotics. The Nature publication reporting on the discovery of teixobactin traces the complete development cascade of an antibiotic from the isolation of the strain to initial pharmacological compound profiling in animal models. The cultivation of the bacterial producer, which originates from soil, was based on the sophisticated iChip technology dedicated to the investigation of microorganisms previously considered as “uncultivable”. Bacterial cultures were contained in a “non-natural” diffusion chamber, but also had contact to their natural sediment environment through a semipermeable membrane. This membrane enabled the supply of natural nutrients and growth factors. A sufficiently high dilution at the beginning of this procedure secured the presence of only a single bacterial cell per compartment of the chip. The extract of the previously unknown Gram-negative b-proteobacterium Eleftheria terrae attracted attention, as it inhibited the growth of the problematic pathogen Staphylococcus aureus. The subsequent activity-based isolation led to the discovery of teixobactin, the structure of which was elucidated by mass spectrometry, amino acid analysis, and NMR-spectroscopy (Scheme 1). Teixobactin (1) is an undecapeptide of moderate structural complexity. The peptide is characterized by a cyclotetradepsipeptide substructure formed by lactonization at the C terminus of Thr-Ile. Apart from d-amino acids and NMe-Phe, the uncommon amino acid enduracididin (End) is present, which is also a constituent of the peptide antibiotic mannopeptimycin (2). The analysis of sequence data allowed the assignment of a nonribosomal peptide synthesis to teixobactin. The relatively high molecular mass of teixobactin (1242 gmol¢1) hints toward the cell-wall biosynthesis as a likely molecular target. Indeed, in addition to lipid III (6), a building block of the wall teichoic acid biosynthesis, namely lipid II (5), seems to be the main target of teixobactin (Scheme 2). Remarkably, in this case it is not an enzyme that [*] Dr. F. von Nussbaum Global Drug Discovery, Medicinal Chemistry Berlin Bayer HealthCare (Germany) E-mail: franz.nussbaum@bayer.com