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Self-replicating chemical systems have been designed and studied to identify the minimal requirements for molecular replication, to translate the principle into synthetic supramolecular systems and to derive a better understanding of the scope and limitations of self-organization processes that are believed to be relevant to the origin of life on Earth. Current implementations make use of oligonucleotide analogues, peptides, and other molecules as templates and are based either on autocatalytic, cross-catalytic, or collectively catalytic pathways for template formation. A common problem of these systems is product inhibition, leading to parabolic instead of exponential amplification. The latter is the dynamic prerequisite for selection in the darwinian sense. We here describe an iterative, stepwise procedure for chemical replication which permits an exponential increase in the concentration of oligonucleotide analogues. The procedure employs the surface of a solid support and is called SPREAD (surface-promoted replication and exponential amplification of DNA analogues). Copies are synthesized from precursor fragments by chemical ligation on immobilized templates, and then liberated and immobilized to become new templates. The process is repeated iteratively. The role of the support is to separate complementary templates which would form stable duplexes in solution. SPREAD combines the advantages of solid-phase chemistry with chemical replication, and can be further developed for the non-enzymatic and enzymatic amplification of RNA, peptides and other templates as well as for studies of in vitro evolution and competition in artificial chemical systems. Similar processes may also have played a role in the origin of life on Earth, because the earliest replication systems may have proliferated by spreading on mineral surfaces.

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This review covers some of the recent progress in the field of peptide antibiotics with a focus on compounds with novel or established mode of action and with demonstrated efficacy in animal infection models. Novel drug discovery approaches, linear and macrocyclic peptide antibiotics, lipopeptides like the polymyxins as well as peptides addressing targets located in the plasma membrane or in the outer membrane of bacterial cells are discussed.

The α-ketoacid–hydroxylamine (KAHA) ligation enables the direct cyclization of unprotected peptides upon cleavage, without coupling reagents or purification of precursors. We report the synthesis of a library of 24 cyclic peptides and a detailed mechanistic study.

Polymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact with lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize the interaction of polymyxins with native, LPS-containing outer membrane patches of Escherichia coli by high-resolution atomic force microscopy imaging, along with structural and biochemical assays. We find that polymyxins arrange LPS into hexagonal assemblies to form crystalline structures. Formation of the crystalline structures is correlated with the antibiotic activity, and absent in polymyxin-resistant strains. Crystal lattice parameters alter with variations of the LPS and polymyxin molecules. Quantitative measurements show that the crystalline structures decrease membrane thickness and increase membrane area as well as stiffness. Together, these findings suggest the formation of rigid LPS–polymyxin crystals and subsequent membrane disruption as the mechanism of polymyxin action and provide a benchmark for optimization and de novo design of LPS-targeting antimicrobials.

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Dedicated to Jack Dunitz, teacher, colleague, and friend, on the occasion of his 80th birthday Among the members of a family of diastereoisomeric pentopyranosyl-(4' 3 2')-oligonucleotide systems derived from d-ribose, d-xylose, l-lyxose, and l-arabinose, the a-arabinopyranosyl system shows by far the strongest WatsonÀCrick base pairing. The system is, in fact, one of the strongest oligonucleotide-type basepairing systems known. It undergoes efficient cross-pairing with all the other members of the pentopyranosyl family, but not with RNA and DNA. The paper describes the synthesis and pairing of the properties of a-larabinopyranosyl-(4' 3 2')-oligonucleotides.Helvetica Chimica Acta ± Vol. 86 (2003) 1259 the synthesis and the pairing behavior of a-dand a-l-arabinopyranosyl-(4' 3 2')oligonucleotides, complementing the two preliminary publications on the topic [3a] [3b] and present a discussion of the system in comparison with the other members of the pentopyranosyl-(4' 3 2')-oligonucleotide family. Scheme 1 illustrates the selection problem that arose when choosing the nucleoside configuration for each of the pentopyranosyl nucleoside members for a comparative study of four of the family×s eight members. For the ribopyranosyl member [4], the first studied experimentally, the choice had been straightforward, since, of the two possible nucleoside d-diastereoisomers 4 ), only the b-d-epimer could be expected to exist in a well-defined single-type of conformation. In this isomer, the nucleobase would unambiguously occupy an equatorial position at the pyranosyl chair. Furthermore, the b-d-nucleoside epimer promised to be the more accessible one, since, in this epimer, the nucleobase and the substituents at C(2') are trans to each other. In choosing the other members of the family, the equatorial position of the nucleobase in the more-stable pyranose-chair conformation became the predominant selection criteria by reasons that were both chemical and etiological in nature. According to this criterion, the xylopyranosyl member had obviously to be the b-d-diastereoisomer [1]. Less certain was the choice in the cases of the remaining lyxo-and arabinopyranosyl members, since, for both, it could be expected that, in each of the two epimers, the nucleobase would occupy an equatorial position. In the case of lyxopyranose, the a-l-lyxopyranosyl series was chosen because its nucleosides were expected to be readily accessible (nucleobase trans to substituent at C(2')), and, furthermore, the sense of chirality at the nucleobase-bearing anomeric center is the one corresponding to that in the b-d-riboand b-d-xylopyranosyl series. In the arabinose case, we originally chose to synthesize bd-arabinopyranosyl-nucleosides to be able to study a quartet of pentopyranosyl-(4' 3 2')-oligonucleotides in which the configurational differences between its members would follow a consistent and transparent pattern, allowing a meaningful comparison and interpretation of pairing properties. This pattern would have involved having the phosphodiester grou...