The Molecules Gateway: A Homogeneous, Searchable Database of 150k Annotated Molecules from Actinomycetes.

Natural products are a sustainable resource for drug discovery, but their identification in complex mixtures remains a daunting task. We present an automated pipeline that compares, harmonizes and ranks the annotations of LC-HRMS data by different tools. When applied to 7,400 extracts derived from 6,566 strains belonging to 86 actinomycete genera, it yielded 150,000 molecules after processing over 50 million MS features.

Megalochelin, a Tridecapeptide Siderophore from a Talented Streptomycete.

Streptomycetes are bacteria known for their extraordinary biosynthetic capabilities. Herein, we describe the genome and metabolome of a particularly talented strain, Streptomyces ID71268. Its 8.

Allopeptimicins: unique antibacterial metabolites generated by hybrid PKS-NRPS, with original self-defense mechanism in .

In the search for structurally novel metabolites with antibacterial activity, innovative approaches must be implemented to increase the probability of discovering novel chemistry from microbial sources. Here we report on the application of metabolomic tools to the genus , a poorly explored member of the Actinobacteria. From examining extracts derived from 88 isolates belonging to this genus, we identified a family of cyclodepsipeptides acylated with a C polyketide chain, which we named allopeptimicins.

-Acetyl-Cysteinylated Streptophenazines from .

Here, we describe two -acetyl-cysteinylated streptophenazines ( and ) produced by the soil-derived sp. ID63040 and identified through a metabolomic approach. These metabolites attracted our interest due to their low occurrence frequency in a large library of fermentation broth extracts and their consistent presence in biological replicates of the producer strain.

Effective approaches to discover new microbial metabolites in a large strain library.

Natural products have provided many molecules to treat and prevent illnesses in humans, animals and plants. While only a small fraction of the existing microbial diversity has been explored for bioactive metabolites, tens of thousands of molecules have been reported in the literature over the past 80 years. Thus, the main challenge in microbial metabolite screening is to avoid the re-discovery of known metabolites in a cost-effective manner.

Toward Single-Peak Dalbavancin Analogs through Biology and Chemistry.

Glycopeptide antibiotics are used to treat severe multidrug resistant infections caused by Gram-positive bacteria. Dalbavancin is a second generation glycopeptide approved for human use, which is obtained from A40926, a lipoglycopeptide produced by Nonomuraea sp. ATCC39727 as a mixture of biologically active congeners mainly differing in the fatty acid chains present on the glucuronic moiety.

Antibacterial Aromatic Polyketides Incorporating the Unusual Amino Acid Enduracididine.

The increasing incidence of infections caused by drug-resistant pathogens requires new efforts for the discovery of novel antibiotics. By screening microbial extracts in an assay aimed at identifying compounds interfering with cell wall biosynthesis, based on differential activity against a Staphylococcus aureus strain and its isogenic l-form, the potent enduracyclinones (1, 2), containing the uncommon amino acid enduracididine linked to a six-ring aromatic skeleton, were discovered from different Nonomuraea strains. The structures of 1 and 2 were established through a combination of derivatizations, oxidative cleavages, and NMR analyses of natural and C-N-labeled compounds.

Novel Polyethers from Screening Actinoallomurus spp.

In screening for novel antibiotics, an attractive element of novelty can be represented by screening previously underexplored groups of microorganisms. We report the results of screening 200 strains belonging to the actinobacterial genus for their production of antibacterial compounds. When grown under just one condition, about half of the strains produced an extract that was able to inhibit growth of .

Expanding the potential of NAI-107 for treating serious ESKAPE pathogens: synergistic combinations against Gram-negatives and bactericidal activity against non-dividing cells.

Objectives: To characterize NAI-107 and related lantibiotics for their in vitro activity against Gram-negative pathogens, alone or in combination with polymyxin, and against non-dividing cells or biofilms of Staphylococcus aureus. NAI-107 was also evaluated for its propensity to select or induce self-resistance in Gram-positive bacteria.

Methods: We used MIC determinations and chequerboard experiments to establish the antibacterial activity of the examined compounds against target microorganisms.

Antibacterial Paramagnetic Quinones from Actinoallomurus.

Four metabolites, designated paramagnetoquinone A, B, C, and D (1-4), were isolated from three strains belonging to the actinomycete genus Actinoallomurus. Compounds 1 and 2 showed potent antibacterial activity with MIC values lower than 0.015 μg/mL against Gram-positive pathogens, including antibiotic-resistant strains.

Allocyclinones, hyperchlorinated angucyclinones from Actinoallomurus.

A screening program on a limited number of strains belonging to the Actinoallomurus genus yielded a series of new angucyclinones. NMR and MS analyses established that these compounds are characterized by an unusual lactone ring and present up to four halogens per molecule, with one congener representing the first natural product containing a trichloromethyl substitution on an aromatic system. Remarkably, this family of metabolites seems to be produced by phylogenetically distinct Actinoallomurus isolates.

Brominated Variant of the Lantibiotic NAI-107 with Enhanced Antibacterial Potency.

We identified an Actinoallomurus strain producing NAI-107, a chlorinated lantibiotic effective against multidrug-resistant Gram-positive pathogens and previously reported from the distantly related genus Microbispora. Inclusion of KBr in the production medium of either the Actinoallomurus or the Microbispora producer readily afforded brominated variants of NAI-107, which were designated as NAI-108. The other post-translational modifications naturally occurring in this lantibiotic family (i.

Family of class I lantibiotics from actinomycetes and improvement of their antibacterial activities.

Lantibiotics, an abbreviation for "lanthionine-containing antibiotics", interfere with bacterial metabolism by a mechanism not exploited by the antibiotics currently in clinical use. Thus, they have aroused interest as a source for new therapeutic agents because they can overcome existing resistance mechanisms. Starting from fermentation broth extracts preselected from a high-throughput screening program for discovering cell-wall inhibitors, we isolated a series of related class I lantibiotics produced by different genera of actinomycetes.

Pharmacological properties of NAI-603, a well-tolerated semisynthetic derivative of ramoplanin.

NAI-603 is a ramoplanin derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml.

A glycosylated, labionin-containing lanthipeptide with marked antinociceptive activity.

Among the growing family of ribosomally synthesized, post-translationally modified peptides, particularly intriguing are class III lanthipeptides containing the triamino acid labionin. In the course of a screening program aimed at finding bacterial cell wall inhibitors, we discovered a new lanthipeptide produced by an Actinoplanes sp. The molecule, designated NAI-112, consists of 22 amino acids and contains an N-terminal labionin and a C-terminal methyl-labionin.

Capturing linear intermediates and C-terminal variants during maturation of the thiopeptide GE2270.

Thiopeptides are ribosomally synthesized, posttranslationally modified peptides with potent activity against Gram-positives. However, only GE2270 has yielded semisynthetic derivatives under clinical investigations. The pbt gene cluster from the GE2270 producer Planobispora rosea was successfully expressed in the genetically tractable Nonomuraea ATCC39727.

Efficacy of the new lantibiotic NAI-107 in experimental infections induced by multidrug-resistant Gram-positive pathogens.

NAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate the in vivo efficacy of NAI-107 in animal models of severe infection.

Synthesis and preliminary biological characterization of new semisynthetic derivatives of ramoplanin.

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously.

Importance of the structure of vancomycin binding pocket in designing compounds active against vancomycin-resistant enterococci (VRE).

16-Membered meta, para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) are designed and synthesized. The structural features of these biaryl ether containing macrocycles are: a) the deletion of the carboxyl group of vancomycin's central amino acid (amino acid D); b) the elongation of the N-terminal; c) the presence of lipidated aminoglucose at the D-ring. Cycloetherification by way of an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as a key step for the construction of the macrocycle.

Design and synthesis of simple macrocycles active against vancomycin-resistant enterococci (VRE).

16-membered meta,para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) were designed and synthesized. The structural key features of these biaryl ether containing macrocycles are (1) the presence of beta-amino-alpha-hydroxy acid or alpha,beta-diamino acid as the C-terminal component of the cyclopeptide and (2) the presence of a hydrophobic chain or lipidated aminoglucose at the appropriate position. Cycloetherification by an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as the key step for the construction of the macrocycle.

Identification of synthetic compounds active against VRE: the role of the lipidated aminoglucose and the structure of glycopeptide binding pocket.

A modified vancomycin binding pocket (D-O-E ring) incorporating an alpha-hydroxy-beta-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 microg/ml against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for the anti-VRE activities.

Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. Part 3: Chemical derivatization.

GE23077 is a novel RNA polymerase inhibitor that is isolated from the fermentation broth of an Actinomadura sp. It is a cyclic heptapeptide complex made up of four factors, differing in the structure of acyl group connected to the side chain of an alpha,beta-diaminopropanoic acid moiety and in the configuration of the stereocenter of an alpha-amino-malonic acid residue. Although GE23077 shows strong inhibitory activity on both Rifampicin-sensitive and -resistant polymerases, it exhibits poor antimicrobial activity.

Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between d-Ala-d-Lac binding and hydrophobic effect.

A modified vancomycin binding pocket (D-O-E ring) incorporating a CHNHCOR function at the AA4 position is designed and synthesized. Potent bioactivities against both sensitive- and resistant-strain are found for some of these compounds (MIC 4 microg/mL against VREF). From this preliminary SAR studies, it was speculated that the D-Ala-D-Ala binding was required for this series of compounds since the corresponding des-leucine derivative is inactive.

Efficacy of dalbavancin against methicillin-resistant Staphylococcus aureus in the rat granuloma pouch infection model.

Infections due to methicillin-resistant Staphylococcus aureus (MRSA) are an important cause of morbidity and mortality in hospital patients. Moreover, increased incidences of outpatient MRSA have been recently reported. This study investigated the bactericidal activity of dalbavancin, a novel, semisynthetic glycopeptide antibiotic, against methicillin-sensitive S.