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Methodological Developments in Marine Natural Product Sciences—A Themed Issue in Honor of Professor William Fenical

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 25686

Special Issue Editors

Dept. Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 900 S. Ashland Ave, MBRB Room 3120, MC 870, Chicago, IL 60607, USA
Interests: microorganisms; antibiotic discovery; microbial library generation; bioinformatics
College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Interests: marine natural products; cyanobacteria; chemical biology; drug discovery and development

Special Issue Information

Dear Colleagues,

Professor William Fenical has made indispensable contributions to the field of marine natural products. In particular, he pioneered methods to sample the marine environment and make it accessible to academic researchers, shed light on the vast microbial biodiversity that is specific to the ocean, and helped lay the foundation for modern microbial natural product discovery. These, in addition to his decades of successful mentoring, leave a continuing footprint in the current effort to understand both fundamental basic science questions and the potential contribution of the marine environment to improve human health. In the spirit of his vast contributions to the field, we welcome submissions that aim to innovate or expand on the following topics: environmental sampling, methods to rapidly assess biological diversity from the environment, natural product discovery from understudied microbial genera, marine pharmacology, mechanism of action studies, and general improvements to the drug discovery process (including but not limited to innovative screening tools, new biological targets, genomic bioinformatics, and addressing the drug-lead supply issue).   

Sincerely,

Prof. Dr. Brian T. Murphy
Prof. Dr. Hendrik Luesch
Guest Editors

Manuscript Submission Information

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Keywords

  • Biological and microbial diversity
  • Methodology
  • Marine pharmacology
  • Drug discovery

Published Papers (11 papers)

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Research

7 pages, 1937 KiB  
Communication
Automated Microbial Library Generation Using the Bioinformatics Platform IDBac
by Chase M. Clark, Linh Nguyen, Van Cuong Pham, Laura M. Sanchez and Brian T. Murphy
Molecules 2022, 27(7), 2038; https://doi.org/10.3390/molecules27072038 - 22 Mar 2022
Cited by 2 | Viewed by 2324
Abstract
Libraries of microorganisms have served as a cornerstone of therapeutic drug discovery, though the continued re-isolation of known natural product chemical entities has remained a significant obstacle to discovery efforts. A major contributing factor to this redundancy is the duplication of bacterial taxa [...] Read more.
Libraries of microorganisms have served as a cornerstone of therapeutic drug discovery, though the continued re-isolation of known natural product chemical entities has remained a significant obstacle to discovery efforts. A major contributing factor to this redundancy is the duplication of bacterial taxa in a library, which can be mitigated through the use of a variety of DNA sequencing strategies and/or mass spectrometry-informed bioinformatics platforms so that the library is created with minimal phylogenetic, and thus minimal natural product overlap. IDBac is a MALDI-TOF mass spectrometry-based bioinformatics platform used to assess overlap within collections of environmental bacterial isolates. It allows environmental isolate redundancy to be reduced while considering both phylogeny and natural product production. However, manually selecting isolates for addition to a library during this process was time intensive and left to the researcher’s discretion. Here, we developed an algorithm that automates the prioritization of hundreds to thousands of environmental microorganisms in IDBac. The algorithm performs iterative reduction of natural product mass feature overlap within groups of isolates that share high homology of protein mass features. Employing this automation serves to minimize human bias and greatly increase efficiency in the microbial strain prioritization process. Full article
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9 pages, 1555 KiB  
Article
Anti-Inflammatory Dysidazirine Carboxylic Acid from the Marine Cyanobacterium Caldora sp. Collected from the Reefs of Fort Lauderdale, Florida
by Sarath P. Gunasekera, Sofia Kokkaliari, Ranjala Ratnayake, Thomas Sauvage, Larissa A. H. dos Santos, Hendrik Luesch and Valerie J. Paul
Molecules 2022, 27(5), 1717; https://doi.org/10.3390/molecules27051717 - 06 Mar 2022
Cited by 6 | Viewed by 2155
Abstract
Dysidazirine carboxylic acid (1) was isolated from the lipophilic extract of a collection of the benthic marine cyanobacterium Caldora sp. from reefs near Fort Lauderdale, Florida. The planar structure of this new compound was determined by spectroscopic methods and comparisons between [...] Read more.
Dysidazirine carboxylic acid (1) was isolated from the lipophilic extract of a collection of the benthic marine cyanobacterium Caldora sp. from reefs near Fort Lauderdale, Florida. The planar structure of this new compound was determined by spectroscopic methods and comparisons between HRMS and NMR data with its reported methyl ester. The absolute configuration of the single chiral center was determined by the conversion of 1 to the methyl ester and the comparison of its specific rotation data with the two known methyl ester isomers, 2 and 3. Molecular sequencing with 16S rDNA indicated that this cyanobacterium differs from Caldora penicillata (Oscillatoriales) and represents a previously undocumented and novel Caldora species. Dysidazirine (2) showed weak cytotoxicity against HCT116 colorectal cancer cells (IC50 9.1 µM), while dysidazirine carboxylic acid (1) was non-cytotoxic. Similar cell viability patterns were observed in RAW264.7 cells with dysidazirine only (2), displaying cytotoxicity at the highest concentration tested (50 µM). The non-cytotoxic dysidazirine carboxylic acid (1) demonstrated anti-inflammatory activity in RAW264.7 cells stimulated with LPS. After 24 h, 1 inhibited the production of NO by almost 50% at 50 µM, without inducing cytotoxicity. Compound 1 rapidly decreased gene expression of the pro-inflammatory gene iNOS after 3 h post-LPS treatment and in a dose-dependent manner (IC50 ~1 µM); the downregulation of iNOS persisted at least until 12 h. Full article
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11 pages, 2282 KiB  
Communication
Accessing Nystatin through Mariculture
by James J. La Clair
Molecules 2021, 26(24), 7649; https://doi.org/10.3390/molecules26247649 - 17 Dec 2021
Cited by 2 | Viewed by 1886
Abstract
Understanding our oceans and their marine ecosystems has enabled the development of sustainable systems for mariculture. While the bulk of studies to date have focused on the production of food, its remarkable expanse has inspired the translation of other markets towards aquatic environments. [...] Read more.
Understanding our oceans and their marine ecosystems has enabled the development of sustainable systems for mariculture. While the bulk of studies to date have focused on the production of food, its remarkable expanse has inspired the translation of other markets towards aquatic environments. This manuscript outlines an approach to pharmaceutical mariculture, by demonstrating a benchmark for future prototyping. Here, design, field evaluation and natural product chemistry are united to successfully produce nystatin at sea. This study begins by evaluating new designs for culture flasks, illustrating a next step towards developing self-contained bioreactors for culturing in marine environments. Through pilot studies, an underwater system was developed to cost effectively produce cultures that yielded 200 mg of nystatin per deployment. Overall, this study demonstrates the potential for the practical culturing of microbes in a marine environment and provides an important next step for the fledgling field of molecular mariculture. Full article
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9 pages, 2489 KiB  
Article
Isolation and Identification of Pentalenolactone Analogs from Streptomyces sp. NRRL S-4
by Huanhuan Li, Hongji Li, Shuo Chen, Wenhui Wu and Peng Sun
Molecules 2021, 26(23), 7377; https://doi.org/10.3390/molecules26237377 - 05 Dec 2021
Cited by 5 | Viewed by 1828
Abstract
Terpene synthases are widely distributed in Actinobacteria. Genome sequencing of Streptomyces sp. NRRL S-4 uncovered a biosynthetic gene cluster (BGC) that putatively synthesizes pentalenolactone type terpenes. Guided by genomic information, the S-4 strain was chemically investigated, resulting in the isolation of two new [...] Read more.
Terpene synthases are widely distributed in Actinobacteria. Genome sequencing of Streptomyces sp. NRRL S-4 uncovered a biosynthetic gene cluster (BGC) that putatively synthesizes pentalenolactone type terpenes. Guided by genomic information, the S-4 strain was chemically investigated, resulting in the isolation of two new sesquiterpenoids, 1-deoxy-8α-hydroxypentalenic acid (1) and 1-deoxy-9β-hydroxy-11-oxopentalenic acid (2), as shunt metabolites of the pentalenolactone (3) biosynthesis pathway. Their structures and absolute configurations were elucidated by analyses of HRESIMS and NMR spectroscopic data as well as time-dependent density functional theory/electronic circular dichroism (TDDFT/ECD) calculations. Compounds 1 and 2 exhibited moderate antimicrobial activities against Gram-positive and Gram-negative bacteria. These results confirmed that the pentalenolactone pathway was functional in this organism and will facilitate efforts for exploring Actinobacteria using further genome mining strategies. Full article
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15 pages, 3009 KiB  
Article
Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas
by Amanda S. Hirata, Paula Rezende-Teixeira, João Agostinho Machado-Neto, Paula C. Jimenez, James J. La Clair, William Fenical and Leticia V. Costa-Lotufo
Molecules 2021, 26(23), 7362; https://doi.org/10.3390/molecules26237362 - 04 Dec 2021
Cited by 4 | Viewed by 2075
Abstract
Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility [...] Read more.
Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of SQ1 in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue SQ2 showed improved solubility and reached a 30–40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to SQ1 and SQ2, whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors. Full article
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24 pages, 3927 KiB  
Article
A Meta-Omics Analysis Unveils the Shift in Microbial Community Structures and Metabolomics Profiles in Mangrove Sediments Treated with a Selective Actinobacterial Isolation Procedure
by Miguel David Marfil-Santana, Anahí Martínez-Cárdenas, Analuisa Ruíz-Hernández, Mario Vidal-Torres, Norma Angélica Márquez-Velázquez, Mario Figueroa and Alejandra Prieto-Davó
Molecules 2021, 26(23), 7332; https://doi.org/10.3390/molecules26237332 - 02 Dec 2021
Cited by 4 | Viewed by 2089
Abstract
Mangrove sediment ecosystems in the coastal areas of the Yucatan peninsula are unique environments, influenced by their karstic origin and connection with the world’s largest underground river. The microbial communities residing in these sediments are influenced by the presence of mangrove roots and [...] Read more.
Mangrove sediment ecosystems in the coastal areas of the Yucatan peninsula are unique environments, influenced by their karstic origin and connection with the world’s largest underground river. The microbial communities residing in these sediments are influenced by the presence of mangrove roots and the trading chemistry for communication between sediment bacteria and plant roots can be targeted for secondary metabolite research. To explore the secondary metabolite production potential of microbial community members in mangrove sediments at the “El Palmar” natural reserve in Sisal, Yucatan, a combined meta-omics approach was applied. The effects of a cultivation medium reported to select for actinomycetes within mangrove sediments’ microbial communities was also analyzed. The metabolome of the microbial communities was analyzed by high-resolution liquid chromatography-tandem mass spectrometry, and molecular networking analysis was used to investigate if known natural products and their variants were present. Metagenomic results suggest that the sediments from “El Palmar” harbor a stable bacterial community independently of their distance from mangrove tree roots. An unexpected decrease in the observed abundance of actinomycetes present in the communities occurred when an antibiotic-amended medium considered to be actinomycete-selective was applied for a 30-day period. However, the use of this antibiotic-amended medium also enhanced production of secondary metabolites within the microbial community present relative to the water control, suggesting the treatment selected for antibiotic-resistant bacteria capable of producing a higher number of secondary metabolites. Secondary metabolite mining of “El Palmar” microbial community metagenomes identified polyketide synthase and non-ribosomal peptide synthetases’ biosynthetic genes in all analyzed metagenomes. The presence of these genes correlated with the annotation of several secondary metabolites from the Global Natural Product Social Molecular Networking database. These results highlight the biotechnological potential of the microbial communities from “El Palmar”, and show the impact selective media had on the composition of communities of actinobacteria. Full article
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16 pages, 12657 KiB  
Article
Chemical Diversity and Antimicrobial Potential of Cultivable Fungi from Deep-Sea Sediments of the Gulf of Mexico
by Rodrigo Villanueva-Silva, Patricia Velez, Meritxell Riquelme, Carlos A. Fajardo-Hernández, Anahí Martínez-Cárdenas, Alejandra Arista-Romero, Baojie Wan, Rui Ma, Mallique Qader, Scott G. Franzblau and Mario Figueroa
Molecules 2021, 26(23), 7328; https://doi.org/10.3390/molecules26237328 - 02 Dec 2021
Cited by 3 | Viewed by 2336
Abstract
A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the “one strain, many compounds” approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, [...] Read more.
A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the “one strain, many compounds” approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.3% of the variation. The bioactivity-guided and conventional chemical studies of selected fungal strains allowed the identification of several active and specialized metabolites. Finally, metabolomics analysis by GNPS molecular networking and manual dereplication revealed the biosynthetic potential of these species to produce interesting chemistry. This work uncovers the chemical and biological study of marine-derived fungal strains from deep-sea sediments of the Gulf of Mexico. Full article
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11 pages, 1525 KiB  
Article
Lentzeacins A-E, New Bacterial-Derived 2,5- and 2,6-Disubstituted Pyrazines from a BGC-Rich Soil Bacterium Lentzea sp. GA3-008
by Hong-Bing Liu, Jack R. Davison, Rahim Rajwani, Gengxiang Zhao, Shannon I. Ohlemacher, Robert D. O’Connor and Carole A. Bewley
Molecules 2021, 26(23), 7197; https://doi.org/10.3390/molecules26237197 - 27 Nov 2021
Viewed by 1812
Abstract
Pyrazines (1,4-diazirines) are an important group of natural products that have tremendous monetary value in the food and fragrance industries and can exhibit a wide range of biological effects including antineoplastic, antidiabetic and antibiotic activities. As part of a project investigating the secondary [...] Read more.
Pyrazines (1,4-diazirines) are an important group of natural products that have tremendous monetary value in the food and fragrance industries and can exhibit a wide range of biological effects including antineoplastic, antidiabetic and antibiotic activities. As part of a project investigating the secondary metabolites present in understudied and chemically rich Actinomycetes, we isolated a series of six pyrazines from a soil-derived Lentzea sp. GA3-008, four of which are new. Here we describe the structures of lentzeacins A-E (1, 3, 5 and 6) along with two known analogues (2 and 4) and the porphyrin zincphyrin. The structures were determined by NMR spectroscopy and HR-ESI-MS. The suite of compounds present in Lentzea sp. includes 2,5-disubstituted pyrazines (compounds 2, 4, and 6) together with the new 2,6-disubstituted isomers (compounds 1, 3 and 5), a chemical class that is uncommon. We used long-read Nanopore sequencing to assemble a draft genome sequence of Lentzea sp. which revealed the presence of 40 biosynthetic gene clusters. Analysis of classical di-modular and single module non-ribosomal peptide synthase genes, and cyclic dipeptide synthases narrows down the possibilities for the biosynthesis of the pyrazines present in this strain. Full article
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13 pages, 1471 KiB  
Article
GPCR Pharmacological Profiling of Aaptamine from the Philippine Sponge Stylissa sp. Extends Its Therapeutic Potential for Noncommunicable Diseases
by Harmie Luyao, Hendrik Luesch and Mylene Uy
Molecules 2021, 26(18), 5618; https://doi.org/10.3390/molecules26185618 - 16 Sep 2021
Cited by 2 | Viewed by 2578
Abstract
We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to [...] Read more.
We report the first isolation of the alkaloid aaptamine from the Philippine marine sponge Stylissa sp. Aaptamine possessed weak antiproliferative activity against HCT116 colon cancer cells and inhibited the proteasome in vitro at 50 µM. These activities may be functionally linked. Due to its known, more potent activity on certain G-protein coupled receptors (GPCRs), including α-adrenergic and δ-opioid receptors, the compound was profiled more broadly at sub-growth inhibitory concentrations against a panel of 168 GPCRs to potentially reveal additional targets and therapeutic opportunities. GPCRs represent the largest class of drug targets. The primary screen at 20 µM using the β-arrestin functional assay identified the antagonist, agonist, and potentiators of agonist activity of aaptamine. Dose-response analysis validated the α-adrenoreceptor antagonist activity of aaptamine (ADRA2C, IC50 11.9 µM) and revealed the even more potent antagonism of the β-adrenoreceptor (ADRB2, IC50 0.20 µM) and dopamine receptor D4 (DRD4, IC50 6.9 µM). Additionally, aaptamine showed agonist activity on selected chemokine receptors, by itself (CXCR7, EC50 6.2 µM; CCR1, EC50 11.8 µM) or as a potentiator of agonist activity (CXCR3, EC50 31.8 µM; CCR3, EC50 16.2 µM). These GPCRs play a critical role in the treatment of cardiovascular disease, diabetes, cancer, and neurological disorders. The results of this study may thus provide novel preventive and therapeutic strategies for noncommunicable diseases (NCDs). Full article
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13 pages, 2384 KiB  
Article
Genome Mining and Molecular Networking-Based Metabolomics of the Marine Facultative Aspergillus sp. MEXU 27854
by Anahí Martínez-Cárdenas, Yuridia Cruz-Zamora, Carlos A. Fajardo-Hernández, Rodrigo Villanueva-Silva, Felipe Cruz-García, Huzefa A. Raja and Mario Figueroa
Molecules 2021, 26(17), 5362; https://doi.org/10.3390/molecules26175362 - 03 Sep 2021
Cited by 3 | Viewed by 2865
Abstract
The marine-facultative Aspergillus sp. MEXU 27854, isolated from the Caleta Bay in Acapulco, Guerrero, Mexico, has provided an interesting diversity of secondary metabolites, including a series of rare dioxomorpholines, peptides, and butyrolactones. Here, we report on the genomic data, which consists of 11 [...] Read more.
The marine-facultative Aspergillus sp. MEXU 27854, isolated from the Caleta Bay in Acapulco, Guerrero, Mexico, has provided an interesting diversity of secondary metabolites, including a series of rare dioxomorpholines, peptides, and butyrolactones. Here, we report on the genomic data, which consists of 11 contigs (N50~3.95 Mb) with a ~30.75 Mb total length of assembly. Genome annotation resulted in the prediction of 10,822 putative genes. Functional annotation was accomplished by BLAST searching protein sequences with different public databases. Of the predicted genes, 75% were assigned gene ontology terms. From the 67 BGCs identified, ~60% belong to the NRPS and NRPS-like classes. Putative BGCs for the dioxomorpholines and other metabolites were predicted by extensive genome mining. In addition, metabolomic molecular networking analysis allowed the annotation of all isolated compounds and revealed the biosynthetic potential of this fungus. This work represents the first report of whole-genome sequencing and annotation from a marine-facultative fungal strain isolated from Mexico. Full article
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16 pages, 1119 KiB  
Article
Total Synthesis of Pagoamide A
by Fusong Wu, Jie Yu, Jiawei Meng, Yian Guo and Tao Ye
Molecules 2021, 26(14), 4224; https://doi.org/10.3390/molecules26144224 - 12 Jul 2021
Cited by 4 | Viewed by 2663
Abstract
The first total synthesis of the thiazole-containing cyclic depsipeptide pagoamide A, is detailed. The longest linear sequence of the liquid-phase synthesis comprises 9 long linear steps from simple known starting materials, which led to the unambiguous structural confirmation of pagoamide A. Full article
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