Tuberculosis (TB) is an infectious airborne disease caused by Mycobacterium tuberculosis. Since the 1990 s, many countries have made significant progress in reducing the incidence of TB and associated mortality by improving health services and strengthening surveillance systems. Nevertheless, due to the emergence of multidrug-resistant TB (MDR-TB), alongside extensively drug-resistant TB (XDR-TB) and TB-HIV co-infection, TB remains one of the lead causes of death arising from infectious disease worldwide, especially in developing countries and disadvantaged populations. Marine natural products (MNPs) have received a large amount of attention in recent years as a source of pharmaceutical constituents and lead compounds, and are expected to offer significant resources and potential in the fields of drug development and biotechnology in the years to come. This review summarizes 169 marine natural products and their synthetic derivatives displaying anti-TB activity from 2013 to the present, including their structures, sources and functions. Partial synthetic information and structure-activity relationships (SARs) are also included.

The filamentous temperature-sensitive mutant Z protein (FtsZ), a key player in bacterial cell division machinery, emerges as an attractive target to tackle the plight posed by the ever growing antibiotic resistance over the world. Therefore in this regard, agents with scaffold diversities and broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens are highly needed. In this study, a new class of marine-derived fascaplysin derivatives has been designed and synthesized by Suzuki-Miyaura cross-coupling. Some compounds exhibited potent bactericidal activities against a panel of Gram-positive (MIC = 0.024-6.25 μg/mL) and Gram-negative (MIC = 1.56-12.5 μg/mL) bacteria including methicillin-resistant S. aureus (MRSA). They exerted their effects by dual action mechanism via disrupting the integrity of the bacterial cell membrane and targeting FtsZ protein. These compounds stimulated polymerization of FtsZ monomers and bundling of the polymers, and stabilized the resulting polymer network, thus leading to the dysfunction of FtsZ in cell division. In addition, these agents showed negligible hemolytic activity and low cytotoxicity to mammalian cells. The studies on docking and molecular dynamics simulations suggest that these inhibitors bind to the hydrophilic inter-domain cleft of FtsZ protein and the insights obtained in this study would facilitate the development of potential drugs with broad-spectrum bioactivities.

Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.

Copper-related reactive oxygen species (ROS) formation can lead to neuropathologic degradation associated with Alzheimer\'s disease (AD) according to amyloid cascade hypothesis. A complexing agent that can selectively chelate with copper ions and capture copper ions from the complex formed by copper ions and amyloid-β (Cu - Aβ complex) may be available in reducing ROS formation. Herein, we described applications of guluronic acid (GA), a natural oligosaccharide complexing agent obtained from enzymatic hydrolysis of brown algae, in reducing copper-related ROS formation. UV-vis absorption spectra demonstrated the coordination between GA and Cu(II). Ascorbic acid consumption and coumarin-3-carboxylic acid fluorescence assays confirmed the viability of GA in reducing ROS formation in solutions containing other metal ions and Aβ. Fluorescence kinetics, DPPH radical clearance and high resolution X - ray photoelectron spectroscopy results revealed the reductivity of GA. Human liver hepatocellular carcinoma (HepG2) cell viability demonstrated the biocompatibility of GA at concentrations lower than 320 μM. Cytotoxic results of human neuroblastoma (SH-SY5Y) cells verified that GA can inhibit copper-related ROS damage in neuronal cells. Our findings, combined with the advantages of marine drugs, make GA a promising candidate in reducing copper-related ROS formation associated with AD therapy.

Natural products derived from marine microorganisms have received great attention as a potential resource of new compound entities for drug discovery. The unique marine environment brings us a large group of sulfur-containing natural products with abundant biological functionality including antitumor, antibiotic, anti-inflammatory and antiviral activities. We reviewed all the 484 sulfur-containing natural products (non-sulfated) isolated from marine microorganisms, of which 59.9% are thioethers, 29.8% are thiazole/thiazoline-containing compounds and 10.3% are sulfoxides, sulfones, thioesters and many others. A selection of 133 compounds was further discussed on their structure-activity relationships, mechanisms of action, biosynthesis, and druggability. This is the first systematic review on sulfur-containing natural products from marine microorganisms conducted from January 1987, when the first one was reported, to December 2020.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s42995-021-00101-2.

The increase in antibiotic resistance has made it particularly urgent to develop new antibiotics with novel antibacterial mechanisms. Inhibition of bacterial cell division by disrupting filamentous temperature-sensitive mutant Z (FtsZ) function is an effective and promising approach. A series of novel fascaplysin derivatives with tunable hydrophobicity were designed and synthesized here. The in vitro bioactivity assessment revealed that these compounds could inhibit the tested Gram-positive bacteria including methicillin-resistant S. aureus (MRSA) (MIC = 0.049-25 μg/mL), B. subtilis (MIC = 0.024-12.5 μg/mL) and S. pneumoniae (MIC = 0.049-50 μg/mL). Among them, compounds B3 (MIC = 0.098 μg/mL), B6 (MIC = 0.098 μg/mL), B8 (MIC = 0.049 μg/mL) and B16 (MIC = 0.098 μg/mL) showed the best bactericidal activities against MRSA and no significant tendency to trigger bacterial resistance as well as rapid bactericidal properties. The cell surface integrity of bacteria was significantly disrupted by hydrophobic tails of fascaplysin derivatives. Further studies revealed that these highly active amphiphilic compounds showed low hemolytic activity and cytotoxicity to mammalian cells. Preliminary mechanistic exploration suggests that B3, B6, B8 and B16 are potent FtsZ inhibitors to promote FtsZ polymerization and inhibit GTPase activity of FtsZ, leading to the death of bacterial cells by inhibiting bacterial division. Molecular docking simulations and structure-activity relationship (SAR) study reveal that appropriate increase in the hydrophobicity of fascaplysin derivatives and the addition of additional hydrogen bonds facilitated their binding to FtsZ proteins. These amphiphilic fascaplysin derivatives could serve as a novel class of FtsZ inhibitors, which not only gives new prospects for the application of compounds containing this skeleton but also provides new ideas for the discovery of new antibiotics.

Marine natural products are a discerning arena to search for the future generation of medications to treat a spectrum of ailments. Meanwhile, cancer is becoming more ubiquitous over the world, and the likelihood of dying from it is rising. Surgery, radiation, and chemotherapy are the mainstays of cancer treatment worldwide, but their extensive side effects limit their curative effect. The quest for low-toxicity marine drugs to prevent and treat cancer is one of the current research priorities of researchers. Fucoidan, an algal sulfated polysaccharide, is a potent therapeutic lead candidate against cancer, signifying that far more research is needed. Fucoidan is a versatile, nontoxic marine-origin heteropolysaccharide that has received much attention due to its beneficial biological properties and safety. Fucoidan has been demonstrated to exhibit a variety of conventional bioactivities, such as antiviral, antioxidant, and immune-modulatory characteristics, and anticancer activity against a wide range of malignancies has also recently been discovered. Fucoidan inhibits tumorigenesis by prompting cell cycle arrest and apoptosis, blocking metastasis and angiogenesis, and modulating physiological signaling molecules. This review compiles the molecular and cellular aspects, immunomodulatory and anticancer actions of fucoidan as a natural marine anticancer agent. Specific fucoidan and membranaceous polysaccharides from Ecklonia cava, Laminaria japonica, Fucus vesiculosus, Astragalus, Ascophyllum nodosum, Codium fragile serving as potential anticancer marine drugs are discussed in this review.

Marine natural products are potent and promising sources of drugs among other natural products of plant, animal, and microbial origin. To date, 20 drugs from marine sources are in clinical use. Most approved marine compounds are antineoplastic, but some are also used for chronic neuropathic pain, for heparin overdosage, as haptens and vaccine carriers, and for omega-3 fatty-acid supplementation in the diet. Marine drugs have diverse structural characteristics and mechanisms of action. A considerable increase in the number of marine drugs approved for clinical use has occurred in the past few decades, which may be attributed to increasing research on marine compounds in laboratories across the world. In the present manuscript, we comprehensively studied all marine drugs that have been successfully used in the clinic. Researchers and clinicians are hopeful to discover many more drugs, as a large number of marine natural compounds are being investigated in preclinical and clinical studies.

Methicillin-resistant Staphylococcus aureus (MRSA) is considered as one of the most dangerous clinical pathogens. Biofilms forming ability of MRSA is also a major cause of drug resistance. Hence, it is in urgent need to develop novel antibacterial/antibiofilm drugs. Fascaplysin with a unique cationic five-ring coplanar backbone is emerging as a potential antibacterial compound. In this study, aiming at developing novel and more effective agents, a series of fascaplysin derivatives and their corresponding β-carboline precursors have been synthesized. Then their antibacterial/antibiofilm activity and mechanisms against MRSA were investigated for the first time. The results showed that most fascaplysins rather than β-carboline precursors exhibit superior antimicrobial activity against MRSA ATCC43300, demonstrating the important role of cationic five-ring coplanar backbone playing in antibacterial activity. Among them, 14 and 18 are the most potent compounds with MIC value of 0.098 μg/ml (10-fold lower than vancomycin), and 18 featuring the lowest toxicity. Subsequent mechanisms exploration indicates that 18 has relatively stronger ability to destroy bacterial cell wall and membrane, higher binding affinity to bacterial genomic DNA. Molecular docking study revealed that besides the key role of cationic five-ring coplanar backbone, introduction of N-aryl amide at 9-position of fascaplysin promoted the combination of compound 18 and DNA via additional π-π stacking and hydrogen bonding of the naphthyl group. Moreover, fascaplysins could inhibit MRSA biofilm formation in vitro and bacterial infection in vivo. All these results illustrate that fascaplysin derivative 18 is a strong and safe multi-target antibacterial agent, which makes it an attractive candidate for the treatment of MRSA and its biofilm infections.

Vidarabine (ARA) was one of the earliest marine-related compounds to be used clinically for antiviral therapy, however, its fast metabolism is the main defect of this drug. To overcome this, we designed and synthesized a group of phosphamide-modified ARA compounds using ProTide technology. With a phosphamide modification, these compounds could become the substrate of specific phospholipase enzymes expressed in the liver. Among all 16 synthesized compounds, most showed stronger activity against herpes simplex virus type 1 (HSV-1) than ARA (EC50 of approximately 10 μM). The top three compounds were compound 2 (EC50 = 0.52 ± 0.04 μM), compound 6 (EC50 = 1.05 ± 0.09 μM) and compound 15 (EC50 = 1.18 ± 0.08 μM) (about 2 times higher than Sp type compound 2). This study provides evidence for use of the phosphamide modification, which could give ARA higher activity and liver cell targeting.