Chemical Diversity and Biological Activities of Phaeosphaeria Fungi Genus: A Systematic Review

Microbial natural products (MNPs) have been identified as important hotspots and effective sources for drug lead discovery. The genus Phaeosphaeria (family: Phaeosphaeriaceae, order: Pleosporales), in particular, has produced divergent chemical structures, including pyrazine alkaloids, isocoumarins, perylenequinones, anthraquinones, diterpenes, and cyclic peptides, which display a wide scope of biological potentialities. This contribution comprehensively highlights, over the period 1974–2018, the chemistry and biology of the isolated natural products from the micro-filamentous Phaeosphaeria fungi genus. A list of 71 compounds, with structural and biological diversities, were gathered into 5 main groups.


Introduction
Natural products are a vast and renewable source for novel medicinal products [1][2][3][4][5]. Since the discovery of penicillin in 1928 and streptomycin in 1943, microbial natural products (MNPs) have emerged and have been identified as one of the most powerful prolific sources for drug lead discovery over the past seven decades. Natural product-derived compounds provided impressive and continuous pools for medicinal chemistry applications, and encouraged most of the leading pharmaceutical companies in screening microbial natural extracts for the development of high-throughput libraries [6][7][8]. Recently, the Food and Drug Administration (FDA) declared that natural products and their derivatives represent 38% of all new molecular entities, with 25% coming from microbes, which implies the vital role of microorganisms as a sustainable pipeline in the production of bioactives [7]. Moreover, microbes present a diverse underdeveloped source that extended beyond the terrestrial system to the marine phoma, featuring unusual modes of habitation, including variation in temperature, pressure, acidity, or basicity, which finally affect the structural novelty and complexity. To date, two successful marine microbial natural and synthetic products have been promoted by Nereus Pharmaceuticals in advanced clinical trials for cancer treatment, including plinabulin (phase II), which is a fully synthetic analogue base on the natural diketopeprazine alkaloid halimide, isolated from a marine fungus Aspergillus sp., and marizomib "salinosporamide A" (phase I), isolated from the marine actinomycete Salinispora tropica [2]. Phaeosphaeria is a genus of micro-filamentous fungi belonging to the family Phaeosphaeriaceae (order: Pleosporales), a member of Dothideomycetes, the largest fungal taxon. Most of the Phaeosphaeria species are plant pathogens for weeds and grasses. They cause serious infectious, in particular for many important crops plant families like wheat and maize [9]. Early genomic studies were centered only on one species, Phaeosphaeria nodorum. These studies disclosed the presence of 48 biosynthetic gene clusters, including 23 PKS, 14 NPRS, four TS, and five PT. Such a high number of gene clusters implies the high capacity of Phaeosphaeria nodorum as a producing pool for secondary metabolites. However, at present, only two biosynthetic gene clusters were connected to their metabolites, including SN477 (for isocoumarins-mellein) and SnPKS19 (for alternariol) [10][11][12][13]. The Mycobank databases revealed the presence of 208 recorded Phaeosphaeria species, from both terrestrial and marine systems [14]. Phaeosphaeria species have produced a diversity of chemical constituents with a wide scope of biological potentialities including cytotoxicity, antimicrobial, anti-tuberculosis, and antibiotic. To the best of our knowledge, the previous chemical investigations were centered only on five species, including Phaeosphaeria nodorum (Septoria nodorum or Stagonospora nodorum), Phaeosphaeria sp., Phaeosphaeria spartinae, Phaeosphaeria rousseliana, and Phaeosphaeria avenaria. In this communication, we aim to gain the attention of the readers by covering extensively, over the period 1974-2018, the chemical and biological landmarks centered on the microbial natural compounds isolated from the Phaeosphaeria fungi genus (Table 1). Attributively, it is clear that Phaeosphaeria is a significantly rich source for structurally diverse natural compounds, which exhibit a plethora of bioactivities.

Chemistry and Biology of Microbial Natural Products Isolated from the Genus Phaeosphaeria
In this review, we aim to comprehensively document the chemical and biological aspects of the fungal metabolites exclusively isolated from the Phaeosphaeria fungi genus. The isolated compounds are classified into 5 main groups (based on their carbon skeleton) for convenience of handling, and their biological potentialities are enclosed whenever available.

Conclusions and Perspective
A diversity of 71 microbial natural products have been documented. This aforementioned chemical diversity demonstrates that the Phaeosphaeria genus is a rich and promising source for structurally divergent secondary metabolites, with a wide scope of bioactivities. However, the number of isolated compounds, compared to the number of Phaeosphaeria species, implies that it is still an under-investigated research area, worthy of more chemical and pharmacological explorations by natural product scientists.
Author Contributions: A.E.-D. wrote, critically revised, and improved the manuscript.
Acknowledgments: Amr El-Demerdash is grateful to Soizic Prado; head of the fungal natural products research team, French National Museum of Natural History, CNRS-MNHN, Sorbonne Universities Paris, for hosting, supervising, and providing research tools.

Conflicts of Interest:
The author has no conflict of interest.