The total synthesis of pantocin B

[reaction: see text] Pantocin B, an unusual antibiotic produced by Erwinia herbicola, effectively controls E. amylovora, the pathogen causing the plant disease fire blight. A total synthesis of pantocin B from L-alanine, glycine, and L-malic acid is reported.     

Strong Antibiotic Activity of the Myxocoumarin Scaffold in vitro and in vivo

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.     

Structural determination of mannopeptimycin cyclic acetals

In structure-activity relationship (SAR) studies on mannopeptimycin antibiotics, mannopeptimycin α(1) was acetalized by reacting with certain dialkyl acetals under acidic conditions. The major products of these reactions were determined to be cyclic acetals at the 4,6-positions of the terminal mannose (Man-B), by exemplary spectroscopic analyses of two typical acetalization products 2 and 3.     

Biosynthesis of deoxyamphotericins and deoxyamphoteronolides by engineered strains of Streptomyces nodosus

Amphotericin B is an antifungal antibiotic produced by Streptomyces nodosus. During biosynthesis of amphotericin, the macrolactone core undergoes three modifications: oxidation of a methyl branch to a carboxyl group, mycosaminylation, and hydroxylation. Gene disruption was undertaken to block two of these modifications. Initial experiments targeted the amphDIII gene, which encodes a GDP-D-mannose 4,6-dehydratase involved in biosynthesis of mycosamine. Analysis of products by mass spectrometry and NMR indicated that the amphDIII mutant produced 8-deoxyamphoteronolides A and B. This suggests that glycosylation with mycosamine normally precedes C-8 hydroxylation and that formation of the exocyclic carboxyl group can occur prior to both these modifications. Inactivation of the amphL cytochrome P450 gene led to production of novel polyenes with masses appropriate for 8-deoxyamphotericins A and B. These compounds retained antifungal activity and may be useful new antibiotics.     

Synthetic carbapenem antibiotics II. Stereoisomers of 7-hydroxyethyl-2,2,5-trimethyl-3-oxa-1-azabicyclo[4.2.O]octan-8-one

The titled compounds are key synthetic intermediates in the structure-activity relationship studies of novel 1-methyl carbapenem antibiotics. Preparation and structural determination of these stereoisomers by x-ray crystallography and proton NMR spectroscopy are reported.     

Assessing how well a modeling protocol captures a structure-activity landscape

We introduce the notion of structure-activity landscape index (SALI) curves as a way to assess a model and a modeling protocol, applied to structure-activity relationships. We start from our earlier work [ J. Chem. Inf. Model., 2008, 48, 646-658], where we show how to study a structure-activity relationship pairwise, based on the notion of "activity cliffs"-pairs of molecules that are structurally similar but have large differences in activity. There, we also introduced the SALI parameter, which allows one to identify cliffs easily, and which allows one to represent a structure-activity relationship as a graph. This graph orders every pair of molecules by their activity. Here, we introduce the new idea of a SALI curve, which tallies how many of these orderings a model is able to predict. Empirically, testing these SALI curves against a variety of models, ranging over two-dimensional quantitative structure-activity relationship (2D-QSAR), three-dimensional quantitative structure-activity relationship (3D-QSAR), and structure-based design models, the utility of a model seems to correspond to characteristics of these curves. In particular, the integral of these curves, denoted as SCI and being a number ranging from -1.0 to 1.0, approaches a value of 1.0 for two literature models, which are both known to be prospectively useful.     

Environmental DNA-encoded antibiotics fasamycins A and B inhibit FabF in type II fatty acid biosynthesis

In a recent study of polyketide biosynthetic gene clusters cloned directly from soil, we isolated two antibiotics, fasamycins A and B, which showed activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. To identify the target of the fasamycins, mutants with elevated fasamycin A minimum inhibitory concentrations were selected from a wild-type culture of E. faecalis OG1RF. Next-generation sequencing of these mutants, in conjunction with in vitro biochemical assays, showed that the fasamycins inhibit FabF of type II fatty acid biosynthesis (FASII). Candidate gene overexpression studies also showed that fasamycin resistance is conferred by fabF overexpression. On the basis of comparisons with known FASII inhibitors and in silico docking studies, the chloro-gem-dimethyl-anthracenone substructure seen in the fasamycins is predicted to represent a naturally occurring FabF-specific antibiotic pharmacophore. Optimization of this pharmacophore should yield FabF-specific antibiotics with increased potencies and differing spectra of activity. This study demonstrates that culture-independent antibiotic discovery methods have the potential to provide access to novel metabolites with modes of action that differ from those of antibiotics currently in clinical use.     

The structure of hormaomycin and one of its all-peptide aza-analogues in solution: syntheses and biological activities of new hormaomycin analogues

Four new aza-analogues of hormaomycin 1, a secondary metabolite with interesting biological activities produced by Streptomyces griseoflavus, were synthesized and subjected to preliminary tests of their antibiotic activity to provide new insights into the structure-activity relationship studies of this class of compounds. The solution structures of hormaomycin 1 and its aza-analogue 2 a were determined by NMR spectroscopy. The data exhibited a reasonably rigid conformation for both molecules, stabilized by stacking interactions between the aromatic moieties attached to the ring and the side chain. According to NMR-spectral data the aza-analogue epi-2 a has a rather different conformation and indeed shows no antibacterial activity whatsoever.     

Simultaneous arming and structure/activity studies of natural products employing O-H insertions: an expedient and versatile strategy for natural products-based chemical genetics

The identification of "druggable" targets is an immediate opportunity and challenge in the post-genomic era. Natural products are enduring tools for basic cellular studies and leads for identifying medically relevant protein targets. However, their use for these studies is often hampered by limited quantities and a lack of selective and mild monofunctionalization reactions. The development of selective methods that could simultaneously equip the natural product with a reactive group for subsequent conjugation to reporter tags and provide important structure-activity relationship (SAR) information, requiring only a knowledge of functional groups present in the natural product, could significantly decrease the time between bioactive natural product isolation and target identification. Herein, we report such a strategy that enables simultaneous arming and SAR studies of alcohol-containing natural products involving both chemo- and site-selective ("chemosite" selective) and site-nonselective O-H insertion reactions with rhodium carbenoids derived from alkynyl diazo acetates. This strategy was applied to a diverse set of natural products, and general guidelines for predicting chemosite selectivity were formulated. A subsequent Sharpless-Hüisgen [3 + 2] cycloaddition reaction with the appended alkyne allows for attachment of a variety of reporter tags. Using this strategy, we synthesized a novel FK506-biotin conjugate that enabled pull-down of the entire "immunosuppressive complex" including FKBP12, calcineurins A and B, and calmodulin. In addition, the potential for a chemoselective but site-nonselective process was shown with both gibberellic acid methyl ester and brefeldin A using only achiral rhodium catalysts.     

Structure-Activity relationship of MDSA and its derivatives against Staphylococcus aureus Ser/Thr phosphatase Stp1

Ser/thr phosphatase Stp1 is an important virulence factor for Staphylococcus aureus (S. aureus) and plays a key role in its infectivity, suggesting that it could serve as a potential target for treatment of S. aureus infection. Previous studies found that the activity of Stp1 was inhibited by MDSA and its derivatives. In this paper, we used molecular docking, molecular modeling, molecular dynamics simulations, binding free energy decomposition calculations, and hydrogen bond analyses to explore the structure-activity relationship. Energy decomposition indicated that MDSA, hydroxymethyl MDSA, carboxymethyl MDSA and methyl MDSA can bind to the catalytic pocket of Stp1. Furthermore, Met39, Ile163, Ile164, Val167, Gly195 and Asp233 were key residues in the Stp1-inhibitor complexes. Due to the lack of a double salicylate structure, salicylic acid cannot bind to the active site of Stpl, leading to loss of inhibitory activity. Based on these results, the structure-activity relationship at the atomic level was determined, which can promote the development of new and more effective anti-drug resistance inhibitors.     

Synthesis of the anti-Helicobacter pylori agent (+)-spirolaxine methyl ether and the unnatural (2"S)-diastereomer

The first enantioselective synthesis of the anti-Heliocbacter pylori agent (+)-spirolaxine methyl ether 2b has been carried out in a convergent fashion establishing that the absolute stereochemistry of the natural product is in fact (3R, 2"R, 5"R, 7"R) after initial synthesis of the unnatural (2"S)-diastereomer 2a. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycle-activated Julia-Kocienski olefination between benzothiazole-based spiroacetal sulfone 4b and phthalide aldehyde 3a. (2"R, 5"S, 7"S)-Spiroacetal sulfone 4b was prepared via cyclisation of protected dihydroxyketone 6b, which in turn was derived from the coupling of the acetylide derived from (R)-acetylene 24b with aldehyde 3a. Phthalide aldehyde 3a was prepared via intramolecular acylation of bromocarbamate 15, which was available via titanium tetrafluoride-(+)-BINOL-mediated allylation of 3,5-dimethoxybenzaldehyde 13. Union of the sulfone 4b and aldehyde 3a fragments successfully completed the enantioselective synthesis of (+)-spirolaxine methyl ether 2b. The synthesis of the unnatural (3R, 2"S, 5"R, 7"R)-diastereomer of spirolaxine methyl ether 2a was also undertaken in a similar manner by union of phthalide aldehyde 3a with (2"S, 5"S, 7"S)-spiroacetal sulfone 4a derived from (S)-acetylene 24a.     

Total synthesis and antifungal activity of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B

In a study aimed at investigating an as yet unknown structure-activity relationship of the nikkomycin family of antifungal peptidyl nucleoside antibiotics, the present research reports the synthesis and antifungal evaluation of a carbohydrate ring-expanded pyranosyl nucleoside analogue of nikkomycin B. Employing a convergent synthetic route, independent synthesis of the N-terminal amino acid side chain and a stereoselective de novo construction of the desired pyranosyl nucleoside amino acid fragment was followed by peptidic coupling of the two components, leading to the first synthesis of a carbohydrate ring-enlarged pyranosyl nikkomycin B analogue. In vitro biological evaluation of the above analogue against a variety of human pathogenic fungi demonstrated significant antifungal activity against several fungal strains of clinical significance.     

Chimeric streptogramin-tyrocidine antibiotics that overcome streptogramin resistance

Streptogramin antibiotics are comprised of two distinct chemical components: the type A polyketides and the type B cyclic depsipeptides. Clinical resistance to the type B streptogramins can occur via enzymatic degradation catalyzed by the lyase Vgb or by target modification through the action of Erm ribosomal RNA methyltransferases. We have prepared through chemical and chemo-enzymatic approaches a series of chimeric antibiotics composed of elements of type B streptogramins and the membrane-active antibiotic tyrocidine that evade these resistance mechanisms. These new compounds show broad antibiotic activity against gram-positive bacteria including a number of important pathogens, and chimeras appear to function by a mechanism that is distinct from their parent antibiotics. These results allow for the development of a brand new class of antibiotics with the ability to evade type B streptogramin-resistance mechanisms.     

Structural and initial biological analysis of synthetic arylomycin A2

The growing threat of untreatable bacterial infections has refocused efforts to identify new antibiotics, especially those acting by novel mechanisms. While the inhibition of pathogen proteases has proven to be a successful strategy for drug development, such inhibitors are often limited by toxicity due to their promiscuous inhibition of homologous and mechanistically related human enzymes. Unlike many protease inhibitors, inhibitors of the essential type I bacterial signal peptidase (SPase) may be more specific and thus less toxic due to the enzyme's unique structure and catalytic mechanism. Recently, the arylomycins and related lipoglycopeptide natural products were isolated and shown to inhibit SPase. The core structure of the arylomycins and lipoglycopeptides consists of a biaryl-linked, N-methylated peptide macrocycle attached to a lipopeptide tail, and in the case of the lipoglycopeptides, a deoxymannose moiety. Herein, we report the first total synthesis of a member of this group of antibiotics, arylomycin A2. The synthesis relies on Suzuki-Miyaura-mediated biaryl coupling, which model studies suggested would be more efficient than a lactamization-based route. Biological studies demonstrate that these compounds are promising antibiotics, especially against Gram-positive pathogens, with activity against S. epidermidis that equals that of the currently prescribed antibiotics. Structural and biological studies suggest that both N-methylation and lipidation may contribute to antibiotic activity, whereas glycosylation appears to be generally less critical. Thus, these studies help identify the determinants of the biological activity of arylomycin A2 and should aid in the design of analogs to further explore and develop this novel class of antibiotic.     

Molecular mechanics calculations (MM3) on sulfones

The structures of several sulfones, including dimethyl sulfone, methyl ethyl sulfone, methyl vinyl sulfone, and diphenyl sulfone, have been fit with the MM3 force field to existing experimental data from electron diffraction and microwave spectroscopy. The vibrational spectra have also been fit for six of these compounds. The torsional parameters for the aliphatic sulfones were fit to ab initio 6-31G data. Heats of formation were also fit. © 1993 John Wiley & Sons, Inc.     

Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines

Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.     

Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of hsp90

Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitor of DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at approximately 700 microM. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90. Both compounds were significantly more potent than the natural product, and DHN2 proved to be more active than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition, these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reduction in gyrase activity. Thus, we have established the first set of compounds that clearly differentiate between the C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selective Hsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family of antibiotics.     

How does the N-acylation and esterification of amphotericin B molecule affect its interactions with cellular membrane components-the Langmuir monolayer study

This work presents the results of Langmuir monolayers study of two amphotericin B derivatives obtained by N-acylation (N-acetylamphotericin B, Ac-AmB) and esterification (amphotericin B methyl ester, AME) of the parent AmB molecule. The main objective of present investigations was to examine the strength and nature of interactions of Ac-AmB and AME with natural membrane components as compared to AmB, and verify the monolayer results with biological studies in vitro. Our experiments were based on surface pressure-area measurements of mixed monolayers formed by the investigated antibiotics and sterols/DPPC. The interactions were analyzed with the following dependencies: compression modulus-surface pressure, mean molecular area-composition, excess molecular area-composition and excess free energy-composition plots. It has been found that both Ac-AmB and AME form monolayers of a liquid expanded state and their stability is highest as compared to AmB films. The investigated compounds mix in monolayers with natural membrane components within the whole range of the antibiotic mole fraction. The quantitative analysis of the interactions of the investigated antibiotics with sterols and DPPC as well as sterols/DPPC interactions allow us to verify the monolayer results with biological results. A good correlation between both kinds of studies has been found.     

“性质-活性关系”对催化剂研究的方法论意义

"结构-活性关系(SAR)"被普遍看作是催化剂研究的核心问题,但本文强调"性质-活性关系(PAR)"对催化剂研究的方法论意义.此处"性质"指反映催化剂与反应物或中间物相互作用行为的一个参数(例如对中间物的吸附能)或参数组,它是催化剂结构与活性之间的桥梁.因性质与活性之间的联系较结构与活性之间的联系更直接,PAR应比SAR较简单和易得,故PAR更具可行性.一旦通过建立PAR而确定了催化剂的关键性质,就可进而探索此关键性质与结构的关系,即"结构-性质关系(SPR)".作者通过举例说明,PAR与SPR相结合不仅相当于SAR,而且比单独的SAR更能深入理解催化剂本质,并提供更多信息.     

Tobramycin and Nebramine as Pseudo‐oligosaccharide Scaffolds for the Development of Antimicrobial Cationic Amphiphiles

Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo‐oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo‐trisaccharide aminoglycoside tobramycin and its pseudo‐disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure–activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane‐targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use.