A Review: Halogenated Compounds from Marine Actinomycetes

Marine actinomycetes, Streptomyces species, produce a variety of halogenated compounds with diverse structures and a range of biological activities owing to their unique metabolic pathways. These halogenated compounds could be classified as polyketides, alkaloids (nitrogen-containing compounds) and terpenoids. Halogenated compounds from marine actinomycetes possess important biological properties such as antibacterial and anticancer activities. This review reports the sources, chemical structures and biological activities of 127 new halogenated compounds originated mainly from Streptomyces reported from 1992 to 2020.


Introduction
Marine actinomycetes are a rich source of biologically active compounds, which have been widely studied worldwide. They can efficiently produce different secondary metabolites including simple benzene derivatives, polyketides and complex cyclic peptides. These secondary metabolites exhibit a wide range of biological activities including antibacterial, antifungal, anticancer and enzyme inhibition. Most of marine actinomyces were Streptomyces species, but rarer actinomycetes genera have been reported in the past twenty years. Consequently, more novel natural products including new halogenated compounds have been isolated in recent years. According to a review on marine microbial natural products from 2010 to 2013 [1], secondary metabolites from marine actinomycetes possess various structures, including terpenes, peptides, polyketides, alkaloids and halogenated molecules [2]. Due to the high concentration of chloride and bromine ions in seawater, marine actinomycetes usually produce more halogenated compounds than those of their terrestrial counterparts. The majority of the marine halogenated compounds showed certain kind of biological properties including antibacterial and anticancer activities [3]. This review focuses on the sources of marine actinomycetes, structures and biological activities of 127 new halogenated compounds derived from marine-derived actinomycetes from 1992 to 2020.

Summary
According to the summary of halogenated compounds from marine-derived actinomycetes ( Figure 6 and Table 1), the study of halogenated compounds from marine-derived actinomycetes could be traced back to 1992 when marinone (99) was purified from an actinomycete strain CNB-632 isolated from a sediment sample (Table 2) [62]. Since 2005, more new halogenated compounds from marine-derived actinomycetes have been isolated annually than ever before except for 2016. From 2010 to 2014 and in 2020, 10 or more new halogenated compounds were reported annually. By the end of 2020, 127 new halogenated compounds from marine-derived actinomycetes have been reported.    [78] Sediments were the richest source of marine-derived actinomycetes, which produced about 78% of new halogenated compounds (Figure 7). It was reported that sediments are rich in nutrients, which can harbor an enormous quantity of microorganisms, including actinomycetes. It is worth mentioning that, the deeper and older the sediment is, the less abundant the microbes. Nevertheless, marine actinobacteria in sediments will keep providing opportunities for natural product research and natural product drug discovery.
Marine Streptomyces spp. had the highest occurrence of halogenated compounds (98/127 = 77%) (Figure 8), which might be due to their unique and diverse biosynthetic machinery, high halogenase activity or simply Streptomyces being the largest genus of Actinobacteria. Overall, 70.1% of halogenated compounds from marine actinomycetes is biologically active, and 37.3% and 24.6% of the halogenated compounds showed anticancer and antimicrobial activity, respectively ( Figure 9).   The structure types of the new halogenated compounds were diverse, which could be classified as nitrogen-containing compounds, polyketides and terpenoids. Nitrogencontaining compounds and polyketides were two main classes of compounds produced by marine actinomycetes (Figure 10). The number of chlorinated compounds generated by marine actinomycetes is 10 times more than that of brominated compounds (Figure 11), which may be related to the concentrations of chloride and bromide ions in the ocean. Fluorinated natural products were reported before, but no new fluorinated compounds were discovered from marine actinomycetes recently.  In short, marine actinomycetes have unique and diverse biogenetic machinery, which can produce different halogenated compounds with novel structure skeletons and various biological activities, and Streptomyces spp. from sediments are the main producers. Some halogen-containing drugs such as chloramphenicol, vancomycin, chlortetracycline, calicheamicin, rebeccamycin and complestatin have been developed from secondary metabolites isolated from terrestrial actinomycetes [3]. Marine natural products have higher success rate (1 in 3500) in drug discovery, compared with the industry average of 1 in 5000-10,000 compounds [79]. Therefore, halogenated compounds from marine actinomycetes are expected to be a promising source of lead compounds for natural product drug discovery.
Author Contributions: S.C. and C.W. conceived and designed the format of the paper; C.W. and W.D. edited the article; J.L. analyzed the data; H.L. and K.L. drew the structures of the compounds; and S.C. revised the paper. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.