Computational Methods Reveal a Series of Cyclic and Linear Lichenysins and Surfactins from the Vietnamese Marine Sediment-Derived Strain G222.

The strain G222, isolated from a Vietnamese marine sediment, was confidently identified by 16 rRNA gene sequencing. Its AcOEt crude extract was successfully analyzed using non-targeted LC-MS/MS analysis, and molecular networking, leading to a putative annotation of its chemical diversity thanks to spectral libraries from GNPS and metabolite structure prediction obtained from SIRIUS combined with the bioinformatics tool conCISE (Consensus Annotation Propagation of Elucidations). This dereplication strategy allowed the identification of an interesting cluster of a series of putative cyclic and linear lipopeptides of the lichenysin and surfactin families.

Antimicrobial Indole-3-Carboxamido-Polyamine Conjugates Target Bacterial Membranes and Are Antibiotic Potentiators.

Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria ; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties.

Genomes of nine biofilm-forming filamentous strains of Cyanobacteria (genera , and gen. nov.) isolated from mangrove habitats of Guadeloupe (Lesser Antilles).

Biofilm-forming cyanobacteria are abundant in mangrove ecosystems, colonizing various niches including sediment surface and periphyton where they can cover large areas, yet have received limited attention. Several filamentous isolates were recently isolated from Guadeloupe, illustrating the diversity and novelty present in these biofilms. In this study, nine strains belonging to three novel lineages found abundantly in Guadeloupe biofilms are characterized by genome sequencing, morphological and ultrastructural examination, metabolome fingerprinting and searched for secondary metabolites biosynthesis pathways.

Preliminary SAR of Novel Pleuromutilin-Polyamine Conjugates.

While pleuromutilin () and its clinically available derivatives (-) are highly effective against Gram-positive bacteria, they remain inactive against many pathogenic Gram-negative bacteria due to the efflux pump AcrAB-TolC. In an effort to broaden the spectrum of activity of pleuromutilin (), we developed a series of novel pleuromutilin-polyamine conjugates (-) which exhibited promising intrinsic antimicrobial properties, targeting both Gram-positive and Gram-negative bacteria, including , methicillin-resistant (MRSA), and , along with the fungal strain , and were devoid of cytotoxic and hemolytic properties with the exception of one conjugate. Furthermore, this series displayed moderate to low antibiotic potentiation of legacy antibiotics doxycycline and erythromycin, with three conjugates enhancing the activity four-fold in combination with doxycycline.

Indole-3-Acetamido-Polyamines as Antimicrobial Agents and Antibiotic Adjuvants.

The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against and erythromycin against . Compounds , , , , , , , , and exhibited strong growth inhibition of methicillin-resistant (MRSA) and , with minimum inhibitory concentrations (MIC) typically less than 0.

Exploration of Bis-Cinnamido-Polyamines as Intrinsic Antimicrobial Agents and Antibiotic Enhancers.

The marine natural product ianthelliformisamine C is a bis-cinnamido substituted spermine derivative that exhibits intrinsic antimicrobial properties and can enhance the action of doxycycline towards the Gram-negative bacterium . As part of a study to explore the structure-activity requirements of these activities, we have synthesized a set of analogues that vary in the presence/absence of methoxyl group and bromine atoms and in the polyamine chain length. Intrinsic antimicrobial activity towards , methicillin-resistant (MRSA) and the fungus was observed for only the longest polyamine chain examples of non-brominated analogues while all examples bearing either one or two bromine atoms were active.

Structure-Activity Relationship Studies of Indolglyoxyl-Polyamine Conjugates as Antimicrobials and Antibiotic Potentiators.

Antibiotic resistance is a growing global health threat, requiring urgent attention. One approach to overcome antibiotic resistance is to discover and develop new antibiotic enhancers, molecules that work with legacy antibiotics to enhance their efficacy against resistant bacteria. Our previous screening of a library of purified marine natural products and their synthetic analogues led to the discovery of an indolglyoxyl-spermine derivative that exhibited intrinsic antimicrobial properties and was also able to potentiate the action of doxycycline towards the difficult to treat, Gram-negative bacterium .

Investigation of Naphthyl-Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers.

As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. Longer chain (PA-3-12-3) variants containing both 1-naphthyl and 2-naphthyl capping groups exhibited more pronounced intrinsic antimicrobial properties against methicillin-resistant (MRSA) (MIC ≤ 0.

α,ω-Diacyl-Substituted Analogues of Natural and Unnatural Polyamines: Identification of Potent Bactericides That Selectively Target Bacterial Membranes.

In this study, α-ω-disubstituted polyamines exhibit a range of potentially useful biological activities, including antimicrobial and antibiotic potentiation properties. We have prepared an expanded set of diarylbis(thioureido)polyamines that vary in central polyamine core length, identifying analogues with potent methicillin-resistant (MRSA), , and growth inhibition properties, in addition to the ability to enhance action of doxycycline towards Gram-negative bacterium . The observation of associated cytotoxicity/hemolytic properties prompted synthesis of an alternative series of diacylpolyamines that explored aromatic head groups of varying lipophilicity.

Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials.

With the increased incidence of antibiotic resistance, the discovery and development of new antibacterials is of increasing importance and urgency. The report of the natural product antibiotic squalamine in 1993 has stimulated a lot of interest in the study of structurally simplified cholic acid-polyamine derivatives. We report the synthesis of a focused set of deoxycholic acid-polyamine conjugates and the identification of hyodeoxycholic acid derivatives as being potently active towards MRSA and some fungal strains, but with no attendant cytotoxicity or hemolytic properties.

Marine life as a source for breast cancer treatment: A comprehensive review.

Breast cancer, one of the most significant tumors among all cancer cells, still has deficiencies for effective treatment. Moreover, substitute treatments employing natural products as bioactive metabolites has been seriously considered. The source of bioactive metabolites are not only the most numerous but also represent the richest source.

Computational Metabolomics Tools Reveal Subarmigerides, Unprecedented Linear Peptides from the Marine Sponge Holobiont .

A detailed examination of a unique molecular family, restricted to the genus, in a molecular network obtained from an in-house Haplosclerida marine sponge collection (including , , , and species) led to the discovery of subarmigerides, a series of rare linear peptides from , a genus mainly known for polyacetylenes and lipids. The structure of the sole isolated peptide, subarmigeride A () was elucidated through extensive 1D and 2D NMR spectroscopy, HRMS/MS, and Marfey's method to assign its absolute configuration. The putative structures of seven additional linear peptides were proposed by an analysis of their respective MS/MS spectra and a comparison of their fragmentation patterns with the heptapeptide .

Discovery and Preliminary Structure-Activity Investigation of 3-Substituted-1-imidazol-5-yl-1-indoles with In Vitro Activity towards Methicillin-Resistant .

Antibiotics have been the cornerstone of modern medicine saving lives by virtue of being able to cure infectious diseases and to prevent infections in those who are immune compromised. Their intense use has led to a surging increase in the incidence of antibiotic-resistant bacteria resulting in a desperate need for antibiotics with new mechanisms of action. As part of our search for new antimicrobials we have screened an in-house library of compounds and identified two 3-substituted-1-imidazol-5-yl-1-indoles as weak growth inhibitors (MIC 16 µg/mL) against methicillin-resistant (MRSA).

Total Synthesis of the Four Stereoisomers of Cyclo(l-Trp-l-Arg) Raises Uncertainty of the Structures of the Natural Products and Invalidates Their Promising Antimicrobial Activities.

New therapeutic options to combat the growing incidence of antimicrobial resistance are urgently needed. A 2015 publication reported the isolation and biological evaluation of two diketopiperazine natural products, cyclo(l-Trp-l-Arg) (CDP 2) and cyclo(d-Trp-d-Arg) (CDP 3), from an sp. bacterium, finding that the latter metabolite in particular exhibited strong antibacterial activity towards a range of wound-related microorganisms and could synergize the action of ampicillin.

Metabolomics with multi-block modelling of mass spectrometry and nuclear magnetic resonance in order to discriminate Haplosclerida marine sponges.

A comprehensive metabolomic strategy, integrating H NMR and MS-based multi-block modelling in conjunction with multi-informational molecular networking, has been developed to discriminate sponges of the order Haplosclerida, well known for being taxonomically contentious. An in-house collection of 33 marine sponge samples belonging to three families (Callyspongiidae, Chalinidae, Petrosiidae) and four different genera (Callyspongia, Haliclona, Petrosia, Xestospongia) was investigated using LC-MS/MS, molecular networking, and the annotations processes combined with NMR data and multivariate statistical modelling. The combination of MS and NMR data into supervised multivariate models led to the discrimination of, out of the four genera, three groups based on the presence of metabolites, not necessarily previously described in the Haplosclerida order.

Valorisation of the diterpene podocarpic acid - Antibiotic and antibiotic enhancing activities of polyamine conjugates.

As part of our search for new antimicrobials and antibiotic adjuvants, a series of podocarpic acid-polyamine conjugates have been synthesized. The library of compounds made use of the phenolic and carboxylic acid moieties of the diterpene allowing attachment of polyamines (PA) of different lengths to afford a structurally-diverse set of analogues. Evaluation of the conjugates for intrinsic antimicrobial properties identified two derivatives of interest: a PA3-4-3 (spermine) amide-bonded variant 7a that was a non-cytotoxic, non-hemolytic potent growth inhibitor of Gram-positive Staphylococcus aureus (MRSA) and 9d, a PA3-8-3 carbamate derivative that was a non-toxic selective antifungal towards Cryptococcus neoformans.

Repurposing primaquine as a polyamine conjugate to become an antibiotic adjuvant.

In our search for new antibiotic adjuvants as a novel strategy to deal with the emergence of multi-drug resistant (MDR) bacteria, a series of succinylprimaquine-polyamine (SPQ-PA) conjugates and derivatives of a cationic amphiphilic nature have been prepared. Evaluation of these primaquine conjugates for intrinsic antimicrobial properties and the ability to restore the antibiotic activity of doxycycline identified two derivatives, SPQ-PA3-8-3 and SPQ-PA3-10-3 that exhibited intrinsic activity against the Gram-positive bacteria Staphylococcus aureus and the yeast Cryptococcus neoformans. None of the analogues were active against the Gram-negative bacterium Pseudomonas aeruginosa.

The potential role of dietary plant ingredients against mammary cancer: a comprehensive review.

Breast cancer is known as the most devastating cancer in the global female community and is considered as one of the severe health care burdens in both developed and developing countries. In many cases, breast cancer has shown resistance to chemotherapy, radiotherapy and hormonal therapy. Keeping in view these limitations, there is an urgent need to develop safe, readily available and effective breast anticancer treatments.

Spermine Derivatives of Indole-3-carboxylic Acid, Indole-3-acetic Acid and Indole-3-acrylic Acid as Gram-Negative Antibiotic Adjuvants.

The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis-6-bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram-negative bacteria but suffers from being cytotoxic and red-blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole-3-acrylic, indole-3-acetic and indole-3-carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram-negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties.

Functional diversity of microboring Ostreobium algae isolated from corals.

The filamentous chlorophyte Ostreobium sp. dominates shallow marine carbonate microboring communities, and is one of the major agents of reef bioerosion. While its large genetic diversity has emerged, its physiology remains little known, with unexplored relationship between genotypes and phenotypes (endolithic versus free-living growth forms).

New Benthic Cyanobacteria from Guadeloupe Mangroves as Producers of Antimicrobials.

Benthic cyanobacteria strains from Guadeloupe have been investigated for the first time by combining phylogenetic, chemical and biological studies in order to better understand the taxonomic and chemical diversity as well as the biological activities of these cyanobacteria through the effect of their specialized metabolites. Therefore, in addition to the construction of the phylogenetic tree, indicating the presence of 12 potentially new species, an LC-MS/MS data analysis workflow was applied to provide an overview on chemical diversity of 20 cyanobacterial extracts, which was linked to antimicrobial activities evaluation against human pathogenic and ichtyopathogenic environmental strains.

Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines.

A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo- and 6-chloro-indole analogues which also exhibited modest activity (MIC 34-50 μM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E.

A Collection of Bioactive Nitrogen-Containing Molecules from the Marine Sponge .

Thirteen nitrogen-containing molecules (/ and -) were isolated from the Indonesian sponge , highlighting the richness of this organism as a source of alkaloids. Their structures were elucidated using one- and two-dimensional NMR spectroscopy and HR-ESI-MS, while the stereochemistry of the diketopiperazines was established using Marfey's method. All compounds were screened in our standard bioactivity assays, including antibacterial, antikinases, and amyloid β-42 assays.

6-Bromoindolglyoxylamido derivatives as antimicrobial agents and antibiotic enhancers.

The combination of increased incidence of drug-resistant strains of bacteria and a lack of novel drugs in development creates an urgency for the search for new antimicrobials. Initial screening of compounds from an in-house library identified two 6-bromoindolglyoxylamide polyamine derivatives (3 and 4) that exhibited intrinsic antimicrobial activity towards Gram-positive bacteria, Staphylococcus aureus and S. intermedius with polyamine 3 also displaying in vitro antibiotic enhancing properties against the resistant Gram-negative bacterium Pseudomonas aeruginosa.