Antimicrobial compounds from marine Actinomycetes

Abstract

Marine actinomycetes were the main origin of marine natural products in the past forty years. This review was to present the sources, structures and antimicrobial activities of 313 new natural products from marine actinomycetes reported from 1976 to 2019.

Introduction

Marine actinomycetes were the major resource of marine natural products owing to their chemical structures and diverse bioactivities. According to a statistic analysis of marine microbial natural products from 2010 to 2013, marine-derived actinomycetes accounted for 28% (= 253/895) of new marine natural products isolated from microbial origin (Zhao et al. 2013). This review covered the sources, structures and antimicrobial activities of 313 compounds derived from marine actinomycetes reported from 1976 to 2019. These new antimicrobial compounds have diverse chemical structures including polyketides, nitrogen-containing compounds, sterols and terpenoids. Majority of these compounds were antibacterial natural products, which consisted of 87% of the new marine natural products from marine-derived actinomycetes.

Antimicrobial compounds from Streptomyces species

Antimicrobial compounds from Streptomyces sp. associated with sponges

Urauchimycins A and B (1 and 2) (Fig. 1) were isolated from Streptomyces sp. Ni-80. Compounds 1 and 2 exhibited antifungal activity against Candida albicans at 10 μg/mL (Imamura et al. 1993). Eight new antibacterial streptophenazines A–H (3‒10) were obtained from Streptomyces sp. HB202 (Mitova et al. 2008). These compounds showed broad spectrum of inibitory activity against bacterial strains with MIC values ranging from 15.6 to 62.5 μg/mL (Mitova et al. 2008). Mayamycin (11) exhibited antibacterial activity with MIC values ranging from 2.5 to 8.4 μg/mL (Schneemann et al. 2010). Streptophenazine K (12) was isolated from Streptomyces HB202, which showed antibacterial activity against B. subtilis and S. epidermidis with MIC values of 21.6 and 14.5 μM, respectively (Kunz et al. 2014). Streptomyces sp. BCC45596 yielded urdamycinone E (13), urdamycinone G (14), and dehydroxyaquayamycin (15), which were active against M. tuberculosis with MIC values of 3.13, 12.50 and 6.25 μg/mL, respectively (Supong et al. 2012). Jiao et al. isolated four new compounds from Streptomyces sp. LHW52447, namely actinomycins D1−D4 (16–19), which displayed inhibitory activity against S. aureus (MRSA) with MIC values ranging from 0.125 to 1.0  μg/mL (Jiao et al. 2018).

Fig. 1.

Structures of compounds 1–29

Antimicrobial compounds from Streptomyces sp. associated with corals

Four nahuoic acids B–E (20–23) were isolated from Streptomyces sp. SCSGAA 0027, which exhibited weak antibiofilm activity against Shewanella onedensis MR-1 biofilm (Nong et al. 2016). Streptomyces sp. M-207 produced lobophorin K (24), which inhibited S. aureus EPI167 (MRSA) with an MIC₉₀ value in the range of 40−80 μg/mL (Braña et al. 2017a). Anthracimycin B (25) was obtained from a culture of Streptomyces cyaneofuscatus M-169, which displayed antimicrobial activity against S. aureus MRSA (MB5393), S. aureus MSSA (ATCC 29213), E. faecium VANS (CL144754) and E. faecalis VANS (CL144492) with MICs below the lowest concentration tested at 0.03 μg/mL and inhibited M. tuberculosis (H37Ra) with an MIC value of 1−2 μg/mL (Rodríguez et al. 2018). Isotirandamycin B (26) was isolated from a culture of Streptomyces sp. SCSIO 41399, which displayed antimicrobial activity against Streptococcus agalactiae with an MIC value of 11.5 μM (Cong et al. 2019).

Antimicrobial compounds from Streptomyces sp. associated with other marine animals

S. hygroscopicus yielded salinamides A (27) and B (28). Both compounds were active against S. pneumoniae with an equal MIC value of 4 μg/mL. Both compounds were also active against S. pyrogenes with MIC values of 4 and 2 μg/mL, respectively (Trischman et al. 1994). Streptomyces sp. 1053U.I.1a.3b produced lobophorin I (29), which exhibited inhibitory activity against M. tuberculosis and B. subtilis with MIC values of 2.6 and 10.6 μM, respectively (Lin et al. 2014). Salinamide F (30) (Fig. 2) obtained from Streptomyces sp. CNB091, had a broad spectrum of antibacterial activity (Hassan et al. 2015). Streptoseomycin (31) was isolated from Streptomyces seoulensis A01, which exhibited inhibitory activityagainst H. pylori, Lactobacillus acidophilus, Bifidobacterium bifidum, Eubacterium brachy, Propionibacterium acnes, S. aureus, Micrococcus luteus and B. subtilis with MIC values ranging from 2 to 64 μg/mL (Zhang et al. 2018a).

Fig. 2.

Structures of compounds 30–57

Antimicrobial compounds from Streptomyces sp. associated with marine algae

Bisanthraquinone derivatives A−C (32‒34), were isolated from Streptomyces sp. N1–78-1, which displayed antimicrobial activity against MRSA with IC₅₀ values of 0.15, 0.36 and 31 μM, respectively (Socha et al. 2006). 2-Hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl) methyl)-2-propylchroman-4-one (35) was obtained from Streptomyces sp. WR1L1S8, which showed antibacterial activity against E. coli ATCC 25922 and MRSA ATCC 43300 with MIC values of 16 and 2 μM, respectively (Djinni et al. 2013). Braña et al. isolated desertomycin G (36) from Streptomyces althioticus MSM3, which exhibited inhibitory activity against a wide spectrum of bacterial strains, with MIC values ranging from 4 to 64 μg/mL (Braña et al. 2019).

Antimicrobial compounds from Streptomyces sp. associated with mangrove

Divergolides A–D (37–40), were isolated from a culture of Streptomyces sp. HKI0576, which displayed antimicrobial activity against B. subtilis, Mycobacterium vaccae and MRSA with inhibition zone diameters of 10−20 mm (Ding et al. 2011a). Xiamycin B (41), indosespene (42), and sespenine (43) were obtained from Streptomyces sp. HKI0595, which exhibited antibacterial activity against MRSA (Ding et al. 2011b). Kandenols A–E (44‒48) were isolated from Streptomyces sp. HKI0595, which showed weak antimicrobial activity against B. subtilis ATCC 6633 and Mycobacterium vaccae IMET 10670 (Ding et al. 2012). Antimycin B2 (49) was discovered from S. lusitanus XM52, which displayed antibacterial activity against S. aureus and L. hongkongensis with MIC values of 32 and 8 μg/mL, respectively (Han et al. 2012).

Antimicrobial compounds from Streptomyces sp. associated with other plants

Streptomyces sp. MA-12 yielded 7,3’-di-(γ, γ-dimethylallyloxy)-5-hydroxy-4’-methoxyflavone (50). Compound 50 was active against C. musae, G. zeae (Schweinitz) Petch, and P. citrinum at 0.25 mM with inhibition zone diameters of 12.7, 13.00 and 12.17 mm, respectively (Ding et al. 2013). Juanlimycin A (51) was isolated from a culture of Streptomyces sp. LC6, which showed moderate inhibition on the secretion of Salmonella Pathogenicity Island-1 effectors, SipA/B/C/D (Zhang et al. 2014).

Antimicrobial compounds from Streptomyces sp. from marine sediments

Aplasmomycins A−C (52‒54) were isolated from S. griseus SS-20, which inhibited the growth of Gram-positive bacteria (Okami et al. 1976; Sato et al. 1978). Istamycins A and B (55 and 56) were purified from S. tenjimariensis SS-939, which showed inhibition against Gram-positive and Gram-negative bacteria (Okami et al. 1979). Phenazine alkaloid (57) was obtained from a culture of Streptomyces sp. CNB-253, which displayed antimicrobial activity against Hemophilus influenza and Clostridium perfringens with MIC values of 1 and 4 μg/mL, respectively (Pathirana et al. 1992). Wailupemycin A (58) (Fig. 3) and 3-epideoxyenterocin (59) were isolated from Streptomyces sp. BD-26T(20) (Sitachitta et al. 1996). Compound 58 showed antibacterial activity against S. aureus with an inhibition zone diameter of 18 mm at 1 mg/6 mm disk. Compound 59 showed antibacterial activity against E. coli with an inhibition zone diameter of 15 mm at 0.1 mg/6 mm disk. δ-Indomycinone (60) was obtained from Streptomyces sp. B 8300, which showed antibacterial activity against B. subtilis with an MIC value of 100 μg/mL (Biabani et al. 1997). Streptomyces sp. CNB-689 produced actinoflavoside (61), which exhibited wide antibacterial activity against S. pneumonia, S. pyrogenes, S. aureus and M. luteusat with an equal MIC value of 64 μg/mL (Jiang et al. 1997). Dimethyl 5, 10-dihydrophenazine-l,6-dicarboxylate (5, 10-Dihydrophencomycin methyl ester) (62) was isolated from Streptomyces sp. B 8251, which displayed weak antimicrobial activity against E. coli and B. subtilis (Pusecker et al. 1997). Lysophosphatidyl inositols A and B (63 and 64) were isolated from Streptomyces sp. M428, and both compounds showed antifungal activities against C. albican with MIC values of 5.0 and 2.5 μg/mL, respectively (Cho et al. 1999). Lornemide A (65) was discovered from Streptomyces sp. MSTMA190, which demonstrated inhibitory activity against B. subtilitis with a LD₉₉ value of 50 μg/mL (Capon et al. 2000). 2-Amino-9,13-dimethyl heptadecanoic acid (66) was produced by Streptomyces sp. 1010, which showed inhibitory activity against M. luteus and B. subtilis with MIC values of 15 and 50 μg/mL, respectively (Ivanova et al. 2001). A study of Streptomyces sp. B7064 led to the identification of chalcomycin B (67), which displayed antibacterial activity against S. aureus, E. coli and B. subtilis with inhibition zone diameters of 23, 28, and 21 mm at 10 μg/disk, respectively (Asolkar et al. 2002). Bonactin (68) was isolated from Streptomyces sp. BD21–2 and was active against S. aureus, B. megaterium and S. cerevisiae with the inhibition zone diameters of 7.0, 8.0 and 7.5 mm at 1 mg/mL, respectively (Schumacher et al. 2003). Lajollamycin (69) was discovered from S. nodosus NPS007994, which displayed antibacterial activity against S. pneumonia and S. aureus with MIC values of 1.5 and 5 μg/mL, respectively (Manam et al. 2005). Daryamides A and B (70 and 71) was obtained from Streptomyces sp. CNQ-085, which exhibited antifungal activity against C. albicans with MIC values of 62.5 and 125 μg/mL, respectively (Asolkar et al. 2006). 5,7-Dihydroxy-5,6,7,8-tetrahydroazocin-2(1H)-one (72) obtained from Streptomyces sp. QD518 showed inhibitory activity against S. aureus at 40 μg/disc with an inhibition zone diameter of 11 mm (Wu et al. 2006). Streptomyces sp. B8000 yielded 8-hydroxy-3-methoxy-1-propylanthraquinone (73), which was active against S. aureus and Streptomyces viridochromogenes at 40 μg/disc with inhibition zone diameters of 14 and 12 mm, respectively (Poumale et al. 2006). Marinopyrroles A (74) and B (75) were isolated from a culture of Streptomyces sp. CNQ-418, which demonstrated antimicrobial activity against MRSA with MICs of 0.61 and 1.10 μM, respectively (Hughes et al. 2008). Marinopyrrole C (76) displayed antimicrobial activity against MRSA with an MIC value less than 1 μg/mL (Hughes et al. 2010). Streptomyces sp. MS239 produced 77, which showed weak antibacterial activity against B. subtilis ATCC6633 (Motohashi K et al. 2008). Essramycin (78) was obtained from Streptomyces sp. Merv8102, which displayed antibacterial activity against E. coli (ATCC 10536), P .aeruginosa (ATCC 10145), B. subtilis (ATCC6051), S. aureus (ATCC 6538), and M. luteus (ATCC 9341) with the MIC values of 8.0, 3.5, 1.0, 1.0 and 1.5 μg/mL, respectively (El-Gendy et al. 2008). Tirandamycins C (79) was isolated from a culture of Streptomyces sp. 307–9, which demonstrated antimicrobial activity against vancomycin-resistant E. faecalis with an MIC value of 110 μM (Carlson et al. 2009). 8-Deoxyheronamide C (80) was isolated from Streptomyces sp. CMB-M0406, which exhibited inhibitory activity against wild-type fission yeast with an MIC value of 5.8 μM (Sugiyama et al. 2014). Heronapyrroles A−C (81‒83) (Fig. 4) were isolated from Streptomyces sp. CMB-M0423, which inhibited the growth of Gram-positive bacteria with MIC values ranging from 0.6 to 6.5 μM (Raju et al. 2010). Antimycins A₁₉ and A₂₀ (84 and 85) were discovered from S. antibioticus H74–18, which displayed antifungal activity against C. albicans with MIC values of 5 and 10 μg/mL, respectively (Xu et al. 2011). Fijimycins A‒C (86‒88) were obtained from Streptomyces sp. CNS-575, which inhibited the growth of MRSA (ATCC33591, Sanger 252, UAMS1182) with MIC values ranging from 4 to 16 μg/mL (Sun et al. 2011). Glucopiericidin C (89) isolated from Streptomyces sp. B8112 was active against Mucor miehei (Shaaban et al. 2011). Lobophorin F (90) was produced by Streptomyces sp. SCSIO 01127, which demonstrated inhibitory activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with an equal MIC value of 8 μg/mL (Niu et al. 2011). Ansalactams B−D (91‒93) were purified from Streptomyces sp. CNH-189, which exhibited inhibitory activities against MRSA with MIC values of 31.2, 31.2 and 62.5 μg/mL, respectively (Wilson et al. 2011). Three compounds meroindenon (94), merochlorins E (95) and F (96) were produced by Streptomyces sp. CNH-189. Compound 94 displayed antibacterial activity against B. subtilis, K. rhizophila and S. aureus with MIC values of 16, 64 and 128 μg/mL, respectively. Compounds 95 and 96 displayed antibacterial activities against B. subtilis, K. rhizophila and S. aureus with MIC values in the range of 1−2 μg/mL (Ryu et al. 2019). Coumpounds 97 and 98 identified from Streptomyces sp. 211726 were active against C. albicans with MIC values of 2.34 and 12.50 μg/mL, respectively (Yuan et al. 2011). Heronamycin A (99) was produced by Streptomyces sp. CMB-M0392, which displayed inhibition against B. subtilis ATCC6052 and ATCC6633 with MIC values of 8 and 14 μg/mL, respectively (Raju et al. 2012). Bahamaolide A (100) was produced by Streptomyces sp. CNQ343, which showed inhibition against C. albicans and various pathogenic fungi (Kim et al. 2012). Geranylphenazinediol (101) was isolated from Streptomyces sp. LB173, which exhibited weak antibacterial activity (Ohlendorf et al. 2012). Dixiamycins A (102) and B (103), oxiamycin (104) and chloroxiamycin (105) were purified from Streptomyces sp. SCSIO 02999, which demonstrated inhibitory activity against E. coli ATCC 25922 with MIC values of 8, 8, 16 and 4 μg/mL, respectively (Zhang et al. 2012). Compounds 102‒105 also exhibited inhibitory activity against S. aureus ATCC29 213 with MIC values of 8, 16, 16 and 8 μg/mL, respectively. Compounds 102, 103 and 105 displayed inhibitory activity against B. subtilis SCSIO BS01 with MIC values of 64, 128 and 64 μg/mL, respectively. Compounds 102 and 103 showed inhibitory activity against B. thuringiensis SCSIO BT01 with MIC values of 64 and 64 μg/mL, respectively. Streptosetin A (106) was obtained from Streptomyces sp. CP13–10, and it displayed antifungal activity against yeast Sir2p with an MIC value of 2.5 mM (Amagata et al. 2012). Streptomyces sp. RJA2961 was reported to produce novobiocin (107) (Fig. 5), desmethylnovobiocin (108) and 5-hydroxynovobiocin (109), which displayed antibacterial activity against MRSA (ATCC 33591) with MIC values of 0.25, 16 and 8 μg/mL, respectively (Dalisay et al. 2013). Iso-16-deethylindanomycin (110), 16-deethylindanomycin methyl ester (111) and iso-16-deethylindanomycin methyl ester (112) were isolated from a culture of S. antibioticus PTZ0016, which showed antimicrobial activity against S. aureus ATCC6538 with MIC values of 6.0, 6.0 and 8.0 μg/mL, respectively (Lian et al. 2013). Three compounds marfuraquinocins A (113), C and D (114 and 115) were produced by S. niveus SCSIO 3406, and they displayed antibacterial activities against S. aureus ATCC 29213 with an equal MIC value of 8 μg/mL. Compounds 114 and 115 showed antibacterial activities against methicillin-resistant Staphylococcus epidermidis shhs-E₁ with an equal MIC value of 8 μg/mL (Song Y et al. 2013). Streptomyces sp. MS100061 yielded lobophorin G1 (116), which inhibited the growth of B. subtilis and M. tuberculosis H37Rv with MIC values of 3.1 and 32 μg/mL, respectively (Chen et al. 2013). Napyradiomycins A and B (117 and 118) were produced by Streptomyces sp. CNQ-329, which possessed inhibitory activity against MRSA with MIC values of 16 and 64 μg/mL, respectively (Cheng et al. 2013). Designated 4-dehydro-4a-dechlorona pyradiomycin A1 (119), 3-dechloro-3-bromonapyradiomycin A1 (120), and 3-chloro-6,8-dihydroxy-8-α-lapachone (121) from Streptomyces sp. SCSIO 10428 exhibited antibacterial activity against B. thuringensis SCSIO BT01 with MIC values of 8, 1 and 16 μg/mL, respectively. They exhibited antibacterial activity against B. subtilis SCSIOBS01 with MIC values of 4, 1 and 8 μg/mL, respectively (Wu et al. 2013a). Compounds 119 and 120 showed antibacterial activity against S. aureus ATCC 29213 with MIC values of 4.0 and 0.5 μg/mL, respectively. Streptomyces sp. CNH365 afforded anthracimycin (122), which exhibited antibacterial activity against B. anthracis UM23C1–1, S. aureus ATCC, E. faecalis ATCC 29212, S. pneumoniae ATCC 51916 and H. influenzae ATCC 31517 with MIC values of 0.03125, 0.0625, 0.125, 0.25 and 4 μg/mL, respectively (Jang et al. 2013). 11′,12′-Dehydroelaiophylin (123) and 11,11′-O-dimethyl-14′-deethyl-14′-methylelaiophylin (124) were isolated from Streptomyces sp. 7–145, which displayed good inhibitory activity against MRSA and vancomycin-resistant enterococci pathogens (Wu et al. 2013b). Two new compounds ohmyungsamycins A (125) and B (126) were isolated from Streptomyces sp. SNJ042. Compound 125 exhibited inhibitory activity against B. subtilis ATCC6633, K. rhizophila NBRC12708 and P. hauseri NBRC3851 with MIC values of 4.28, 1.07 and 2.14 μM, respectively, while compound 126 was active against K. rhizophila NBRC12708 with an MIC value of 8.5 μM (Um et al. 2013). Lobophorin H (127) was discovered from Streptomyces sp. 12A35, which displayed inhibitory activity against S. aureus ATCC29213 and B. subtilis CMCC63501 with MIC values of 50 and 1.57 μg/mL, respectively (Pan et al. 2013). Mollemycin A (128) was identified from Streptomyces sp. CMBM0244 and it was active against S. aureus ATCC 25293 and ATCC 9144, S. epidermidis ATCC 12228, B. subtilis ATCC 6051 and ATCC 6633, E. coli ATCC 25922, P. aeruginosa ATCC 27853 and Mycobacterium bovis (BCG) with MIC values of 50, 10, 50, 10, 10, 10, 50 and 3200 nM, respectively (Raju et al. 2014). Marformycins A−E (129‒133) exhibited inhibitory activities against M. luteus with MIC values of 0.25, 4.0, 0.25, 0.063 and 4.00 μg/mL, respectively (Zhou et al. 2014). Desotamide B (134) was obtained from a culture of S. scopuliridis SCSIO ZJ46, which demonstrated antimicrobial activity against S. aureus ATCC29213, S. pnuemoniae NCTC 7466 and MRSA with MIC values of 16.0, 12.5 and 32.0 μg/mL, respectively (Song et al. 2014). Glycosylated macrolactins A1 (135) and B1 (136) were isolated from Streptomyces sp. 06CH80, which displayed antibacterial activities against B. subtilis, E. coli, P. aeruginosa, S. aureus and S. cerevisiae with MIC values in the range of 0.027 to 0.22 μM/mL (Mondol et al. 2014). Buanmycin (137) was isolated from Streptomyces sp. SNR69, and compound 137 exhibited antibacterial activity against five bacterial strains with MIC values ranging from 0.7 to 21.1 μg/mL (Moon et al. 2015). Chemical investigation of a culture extract of Streptomyces sp. CMB-M0150 led to the discovery of aranciamycins I (138) (Fig. 6) and J (139). 138 and 139 showed inhibitory activity against M. tuberculosissurrogate with MIC values in the range of 0.7 to 1.7 μM, respectively (Khalil et al. 2015). A fermentation broth of Streptomyces sp. SNM5 yielded mohangamides A (140) and B (141), which exhibited inhibitory activity against C. albicans ICL with IC₅₀ values of 4.4 and 20.5 μM, respectively (Bae et al. 2015a). Hormaomycins B (142) and C (143) from Streptomyces sp. SNM5 displayed broad antibacterial activities with MIC values ranging from 0.23 to 114 μM (Bae et al. 2015b). Streptomyces zhaozhouensis CA-185989 yielded isoikarugamycin (144), 28-N-methylikarugamycin (145), and 30-oxo-28-N-methylikarugamycin (146). 144– 146 were active against MRSA with MIC values of 1–4, 1–4, 32–64 μg/mL, respectively. Compound 144 was active against C. albicans and A. fumigatus with MIC values of 2–4 and 4–8 μg/mL, respectively, and 145 was active against C. albicans and A. fumigatus with MIC values of 4 and 4–8 μg/mL, respectively (Lacret et al. 2015). S. rochei 06CM016 yielded compounds 147 and 148. 147 showed antimicrobial activity against E. coli O157:H7 RSKK 234, MRSA DSM 11729 and C. albicans DSM 5817 with MIC values of 16, 8 and 4 μg/mL, respectively (Aksoy et al. 2016). 148 exhibited antimicrobial activity against E. coli O157:H7 RSKK 234, MRSA DSM 11729 and C. albicans DSM 5817 with MIC values of 16, 16 and 8 μg/mL, respectively (Aksoy et al. 2016). N-acetyl-N-demethylmayamycin (149) was obtained from Streptomyces sp. 182SMLY, which was active against MRSA with an MIC of 20.0 μM (Liang et al. 2016). Neo-actinomycins A (150) and B (151) were discovered from Streptomyces sp. IMB094, which displayed antibacterial activity against MRSA and vancomycin-resistant Enterococci with MIC values in the range of 16 to 64 μg/mL (Wang et al. 2017). Strepchazolin A (152) was obtained from Streptomyces chartreusis NA02069, which showed antibacterial activity against B. subtilis with an MIC value of 64 μM (Yang et al. 2017). Jiang et al. isolated four new naphthoquinone derivatives from Streptomyces sp. XMA39, namely strepoxepinmycins A–D (153–156), which displayed inhibitory activity against a wide spectrum of strains with MIC values ranging from 6.0 to 10.0 μg/mL (Jiang et al. 2018). Bagremycins F (157) and G (158) were obtained from Streptomyces sp. ZZ745 and they showed inhibitory activities against E. coli with MIC values of 41.8 and 67.1 μM, respectively (Zhang et al. 2018b). Streptomyces Pratensis NA-ZhouS1 yielded stremycins A (159) and B (160). 159 and 160 were active against P. aeruginosa, MRSA, K. pneumonia and E. coli with the same MIC value of 16 μg/mL. Both were also active against B. subtilis with MIC values from 8 to 16 μg/mL (Akhter et al. 2018). Tunicamycin E (161) was obtained from Streptomyces xinghaiensis SCSIO S15077, which exhibited inhibitory activity against B. thuringiensis BT01, B. thuringiensis, C. albicans (ATCC 96901) and C. albicans CMCC (F) 98001 with MIC values of 2.0, 0.5, 32 and 8 μg/mL, respectively (Zhang et al. 2018c). A fermentation broth of Streptomyces sp. ZZ446 yielded a new compound maculosin-O-α-L-rhamnopyranoside (162), which showed antimicrobial activity against MRSA, E. coli and C. albicans with MIC values of 37.0, 28.0 and 26.0 μg/mL, respectively (Chen et al. 2018a). Niphimycins C−E (163−165) and 17-O-methylniphimycin (166) were isolated from a culture of Streptomyces sp. IMB7–145, which displayed antimicrobial activity against C. albican with MIC values of 8−32 μg/mL (Hu et al. 2018). Compound 163 showed anti-bacterial activity against MRSE, MRSA and M. tuberculosis with MIC values ranging from 4 to 64 μg/mL. Streptomyces mutabilis sp. MII yielded N-acetylborrelidin B (167), which was active against B. subtilis, B. cereus and S. aureus with inhibition zone diameters of 8−11 mm. Compound 167 was also active against S. warneri with an inhibition zone diameter of 18 mm (Hamed et al. 2018a). Nivelactam B (168) (Fig. 7), a new biphenyl derivative, was obtained from S. varsoviensis HF-11225, which exhibited inhibitory activity against Sclerotinia sclerotiorum with an inhibition zone diameter of 9 mm at 100 μg per 7 mm paper disks (Chen et al. 2018b). Nosiheptide (169), griseoviridin (170) and etamycin (171) were produced by Streptomyces sp. OPMA 1245. Compound 169 displayed antibacterial activity against M. avium JCM15430, M. intracellulare JCM6384 and M. bovis BCG Pasteur with MIC values of 0.024, 0.024 and 0.012 μg/mL, respectively. Compound 170 showed antibacterial activity against M. avium JCM15430, M. intracellulare JCM6384 and M. bovis BCG Pasteur with MIC values of 1.56, 1.56 and 6.25 μg/mL, respectively. Compound 171 was active against M. avium JCM15430, M. intracellulare JCM6384 and M. bovis BCG Pasteur with MIC values of 0.097, 0.190 and 0.780 μg/mL, respectively (Hosoda et al. 2019). Streptomyces sp. ZZ820 yielded diterpenoids 18-acetyl-cyclooctatin (172), 5,18-dedihydroxy-cyclooctatin (173) and 5-dehydroxy-cyclooctatin (174), which inhibited the growth of MRSA and E. coli with MIC values ranging from 24.11 to 55.12 μM (Yi et al. 2019). Streptomyces sp. G212 produced 2,4-dichlorophenyl 2,4-dichloro benzoate (175) and 4,5-dihydroxy-7-methylphthalide (176). Compound 175 exhibited inhibitory activity against C. albicans with an MIC value of 64 μg/mL, and compound 176 inhibited E. faecalis with the same MIC value of 64 μg/mL (Cao et al. 2019). Streptoglutarimides A–J (177–186) were obtained from Streptomyces sp. ZZ741. 177–186 showed antifungal activity against C. albicans with MIC values in the range of 8−20 μg/mL. They showed inhibitory activity against MRSA with MIC values ranging from 9−11 μg/mL, and against E. coli with MIC values in the range of 8−12 μg/mL (Zhang et al. 2019a). Atratumycin (187) was produced by Streptomyces atratus SCSIOZH16, which displayed inhibition against M. tuberculosis H37Ra and H37Rv with MIC values of 3.8 and 14.6 μM, respectively (Sun et al. 2019).

Fig. 3.

Structures of compounds 58–80

Fig. 4.

Structures of compounds 81–106

Fig. 5.

Structures of compounds 107–137

Fig. 6.

Structures of compounds 138–167

Fig. 7.

Structures of compounds 168–200

Antimicrobial compounds from Streptomyces sp. from marine seawater

Parimycin (188) and trioxacarcins D–F (189–191) obtained from Streptomyces sp. B8652 had a broad spectrum of antibacterial activity (Maskey et al. 2002; Maskey et al. 2004). Streptomyces caelestis afforded new antibacterial citreamicins A (192), B (193), citreaglycon A (194) and dehydrocitreaglycon A (195). 192–195 showed broad spectrum of antibacterial activity against bacterial strains (Liu et al. 2012). Streptcytosine A (196) was discovered from Streptomyces sp. TPU1236A, and it exhibited antibacterial activity against M. smegmatis with an MIC value of 32 μg/mL (Bu et al. 2014).

Antimicrobial compounds from Streptomyces sp. from other marine sources

Streptomyces caniferus CA-271066 afforded caniferolides A–D (197‒200). They showed a broad spectrum of antifungal activity against A. fumigatus ATCC46645 and C. albicans MY1055 with MIC values ranging from 0.5 to 8.0 μg/mL (Pérez-Victoria et al. 2019).

Antimicrobial compounds from Micromonospora species

Antimicrobial compounds from Micromonospora sp. associated with ascidians

Lomaiviticins A (201) (Fig. 8) and B (202) were isolated from Micromonospora lomaivitiensis LL-37I366 and showed inhibitory activities against S. aureus and E. faecium with MIC values in the range of 6 to 25 ng/spot (He et al. 2001). Diazepinomicin (203) was obtained from Micromonospora sp. DPJ12, which exhibited antibacterial activity against Gram-positive bacteria with MICs of about 32 μg/mL (Charan et al. 2004). Micromonohalimane B (204) was isolated from Micromonospora sp. WMMC-218, and 204 inhibited MRSA with an MIC value of 40 μg/mL (Zhang et al. 2016a).

Fig. 8.

Structures of compounds 201–224

Antimicrobial compounds from Micromonospora sp. associated with sponges

Tetrocarcin Q (205) was discovered from Micromonospora carbonacea LS276, which displayed antibacterial activity against B. subitlis ATCC 63501 with an MIC value of 12.5 μM (Gong et al. 2018).

Antimicrobial compounds from Micromonospora sp. from marine sediments

Butremycin (206) was isolated from Micromonospora sp. K310, which exhibited weak antibacterial activity against S. aureus ATCC 25923, E. coli ATCC 2592 and MRSA (Kyeremeh K et al. 2014). Chemical investigation of a culture extract of Micromonospora sp.5–297 led to the discovery of two glycosidic spirotetronates tetrocarcins N (207) and O (208). 207 and 208 showed inhibitory activity against B. subtilis with MIC values of 2 and 64 μg/mL, respectively (Tan et al. 2016). 3,4-Dihydroxy-6,7-dimethyl-quinoline-2-carboxylic acid (209) were isolated from Micromonospora sp. G019, which demonstrated inhibitory activity against E. coli, S. enterica and E. faecalis with the MIC values of 48, 96 and 128 μg/mL, respectively (Thi et al. 2016a). 2-[(5-Methyl-1,4-dioxan-2-yl)methoxy]ethanol (210) showed inhibitory activity against E. faecalis and C. albican with MIC values of 32 and 64 μg/mL, respectively (Thi et al. 2016a). 3-amino-27-demethoxy-27-hydroxyrifamycin S (211), 3-amino-rifamycin S (212), sporalactams A (213) and B (214) were produced by Micromonospora sp. RJA4480. Compounds 211‒214 displayed antibacterial activities against MRSA, E. coli and M. tuberculosis with MIC values of 0.0009, 0.0003 and 0.0009; 0.0008, 0.0001 and 0.0008; 7.0, 1.8 and 0.8; and 1.80, 0.40 and 0.06 μg/mL, respectively (Williams et al. 2017). Microsporanates A–F (215‒220) and tetrocarcin P (221) obtained from Micromonospora harpali SCSIO GJ089 displayed a wide range of antibacterial activities (Gui et al. 2017). Phocoenamicins B (222) and C (223) were isolated from Micromonospora sp. CA-214671, both compounds showed a broad spectrum of antibacterial activities with MIC values ranging from 2 to 64 μg/mL (Pérez-Bonilla et al. 2018).

Antimicrobial compounds from Micromonospora sp. from other marine sources

Thiocoraline (224) was isolated from Micromonospora sp. L-13-ACM2–092, which inhibits the growth of Gram-positive bacteria (Perez et al. 1997).

Antimicrobial compounds from Nocardiopsis species

Antimicrobial compounds from Nocardiopsis sp. from marine sediments

Nocardiopsis dassonvillei produced kahakamide A (225) (Fig. 9), which showed weak antibacterial activity against B. subtilis (Schumacher et al. 2001). Thiopeptide TP-1161 (226) from Nocardiopsis sp. TFS65–07 displayed broad antibacterial activity with MIC values ranging from 0.25 to 1.0 μg/mL (Engelhardt et al. 2010). Nocapyrones E−G (227‒229), were isolated from Nocardiopsis dassonvillei HR10–5, which exhibited inhibitory activities against B. subtilis with MIC values of 26, 14 and 12 μM, respectively (Fu et al. 2011). Nocarimidazoles A (230) and B (231), were produced by Nocardiopsis sp. CNQ115. They displayed antimicrobial activities against B. subtilis with an equal MIC value of 64 μg/mL. Compound 231 displayed antimicrobial activity against S. epidermidis with an MIC value of 64 μg/mL (Leutou et al. 2015). Three α-pyrones 4-deoxyphomapyrone C (232), 4-deoxy-11-methylphomapyrone C (233) and 10-hydroxymucidone (234) were produced by Nocardiopsis sp. SCSIO 10419. Compound 232 displayed antibacterial activity against B. subtilis SCSIO BS01 with an MIC value of 64 μg/mL. Compound 233 and 234 displayed antibacterial activities against M. luteus with the same MIC value of 64 μg/mL (Zhang et al. 2016b). 2-[(2R-Hydroxypropanoyl)amino] benzamide (235) was isolated from Nocardiopsis sp. G057, which displayed inhibitory activity against E. coli with an MIC value of 16 μg/mL (Thi et al. 2016b). Nocazine G (236) was produced by Nocardiopsis sp. YIM M13066, which possessed inhibitory activity against B. subtilis ATCC 6051 with an MIC value of 25.8 μM (Sun et al. 2017). Fluvirucin B6 (237) was isolated from Nocardiopsis sp. CNQ-115, which exhibited inhibitory activity against B. subtilis, K. rhizophila and S. aureus with MIC values of 64, 32 and 32 μg/L, respectively (Leutou et al. 2018). Terretonin N (238) obtained from Nocardiopsis sp. LGO5 had a broad spectrum of antibacterial activity against bacteria (Hamed et al. 2018b).

Fig. 9.

Structures of compounds 225–254

Antimicrobial compounds from Nocardiopsis sp. associated with sponges

Nocardiopsistins A−C (239‒241), were isolated from Nocardiopsis sp. HB-J378, which showed antibacterial activity against MRSA with MIC values ranging from 3.12 to 12.5 μg/mL (Xu et al. 2018).

Antimicrobial compounds from other marine actinomycetes

Antimicrobial compounds from other actinomycetes associated with sponges

2,4,4’-Trichloro-28-hydroxydiphenylether (242) was isolated from Micrococcus luteus, which showed a broad spectrum of antibacterial activity with MIC values ranging from 16 to 64 μg/mL (Bultel-Poncé et al. 1998). Microluside A (243) was obtained from a culture of Micrococcus sp. EG45, which displayed antimicrobial activity against E. faecalis JH212 and S. aureus NCTC 8325 with MIC values of 10 and 13 μM, respectively (Eltamany et al. 2014). PM18110448 (Kocurin) (244) discovered from Kocuria palustris demonstrated a broad spectrum of antibacterial activity (Martín et al. 2013). A study of Actinokineospora spheciospongiae DSM45935^T led to the identification of actinokineosin (245), which exhibited antibacterial activity against M. luteus with an inhibition zone diameter of 8.0 mm at 50 μg/disk (Takasaka et al. 2017).

Antimicrobial compounds from other actinomycetes associated with other marine animals

Saccharothrix espanaensis An 113 produced saccharothrixins A−C (246‒248), which showed modest antibacterial activity (Kalinovskaya et al. 2008). Arenjimycin (249) from Salinispora arenicola CNR-647 displayed broad antibacterial activity (Asolkar et al. 2010). Solwaraspora sp. WMMB329 yielded solwaric acids A and B (250 and 251). Both compounds were active against E. coli, MRSA, MSSA and P. aeruginosa with MIC values of 128, 32, 64, 128 μM and 128, 32, 64, 128 μM, respectively (Ellis et al. 2014). Forazoline A (252) was isolated from Actinomadura sp. WMMB-499, which exhibited inhibitory activity against C. albicans with an MIC value of 16 μg/mL (Wyche et al. 2014). (11S,15R)-11-Hydroxycurvularin (253) and (11R,15R)-11-hydroxycurvularin (254) were obtained from Pseudonocardia sp. HS7. They showed antibacterial activity against E. coli with an equal MIC value of 20 μg/mL (Ye et al. 2016). Actinomadura sp. WMMB499 yielded ecteinamycin (255) (Fig. 10), which showed antibacterial activity against E. coli, S. aureus (MRSA and MSSA), and P. aeruginosa with MIC values of 16, 0.125 and 8 μg/mL, respectively. Compound 255 exhibited inhibition against C. difficile with an MIC value of 0.059−0.117μg/mL (Wyche et al. 2017).

Fig. 10.

Structures of compounds 255–283

Antimicrobial compounds from other actinomycetes associated with mangroves and algae

Lechevalieria aerocolonigenes K10–0216 afforded pyrizomicins A and B (256, 257). They showed broad spectrum of antimicrobial activity (Kimura et al. 2018). Kocuria marina CMG S2 afforded kocumarin (258), which showed activity against MRSA with an MIC value of 10−15 μg/mL (Uzair et al. 2018).

Antimicrobial compounds from other actinomycetes associated with marine sediments

Cultivation of Actinomadura sp. M045 produced three new phenoxazin-3-one antibiotics chandrananimycins A–C (259–261). Compounds 259 and 260 exhibited inhibitory activity against Mucor meihei with inhibition zone diameters of 11 and 12 mm at 20 μg/platelet, respectively. Compound 261 showed activity at 20 μg/platelet against B. subtilis, Mucor meihei and S. aureus with inhibition zone diameters of 23, 27 and 22 mm, respectively (Maskey et al. 2003). Abyssomicin C (262) was obtained from Verrucosispora sp. AB-18–032, which exhibited antibacterial activity against S. aureus N315 and S. aureus Mu50s with MIC values of 4 and 13 μg/mL, respectively (Bister et al. 2004). Chemical investigation of a culture extract of Marinispora sp. CNQ-140 led to the discovery of marinomycins A−D (263−266). These compounds showed inhibitory activity against MRSA with MIC₉₀ values of 0.13, 0.25, 0.25 and 0.25 μM, respectively. Compound 264 showed inhibitory activity against VRFE and C. albicans with MIC₉₀ values of 0.13 and 7.8 μM, respectively (Kwon et al. 2006). Marinispora sp. CNQ-140 produced marinisporolide A (267). 267 displayed antifungal activity against C. albicans with an MIC value of 22 μg/mL (Kwon et al. 2009). Atropabyssomicin C (268) was obtained from Verrucosispora sp. AB-18–032, which showed antibacterial activity against MRSA N315 with an MIC value of 2.67 μg/mL (Keller et al. 2007). Marinispora NPS008920 yielded lipoxazolidinones A‒C (269‒271). These three compounds were active against S. aureus ATCC 29213 (MSSA) and E. faecalis ATCC 29212 (VSE) with MIC values of 0.9, 6.0 and 4.0; and 1.0, 3.0 and 2 μg/mL, respectively. Compound 269 was also active against H. influenza with an MIC value of 12 μg/mL (Macherla et al. 2007). Lynamicins A–E (272–276) were isolated from Marinispora sp. NPS12745, which exhibited inhibitory activity against MRSA and vancomycin-resistant E. faecium with MIC values ranging from 1.8 to 57.0 μg/mL (McArthur et al. 2008). Cultivation of Verrucosispora maris AB-18–032 produced proximicins B and C (277 and 278). Compound 277 showed antibacterial activity against Brevibacillus brevis DSM with an inhibition zone diameter of 12 mm at 0.3 mg/mL, Compound 278 exhibited a slight inhibition against Brevibaccillus brevis DSM30 (Fiedler et al. 2008). Salinisporamycin (279) was isolated from a culture of Salinispora arenicora YM23–082, which displayed antimicrobial activity against B. subtilis IFO 3134 and Salinispora aureus IFO12732 with MIC values of 4.1 and 0.46 μg/mL, respectively (Matsuda et al. 2009). Culture of Salinispora arenicola yielded saliniquinone A (280), which showed weak activity against MRSA (Murphy et al. 2010). Pseudonocardians A–C (281–283) were ontained from Pseudonocardia sp. SCSIO 01299, which exhibited inhibitory activities against S. aureus ATCC 29213, E. faecalis ATCC 29212 and B. thuringensis SCSIO BT01 with MIC values ranging from 1 to 4 μg/mL (Li et al. 2011). Actinoalloteichus sp. NPS702 afforded neomaclafungins A–I (284–292) (Fig. 11). These compounds showed antifungal activity against Trichophyton mentagrophytes (ATCC 9533) with MIC values ranging from 1 to 3 μg /mL (Sato et al. 2012). Marthiapeptide A (293) was isolated from Marinactinospora thermotolerans SCSIO 00652, which inhibited the growth of Gram-positive bacteria with MIC values ranging from 2 to 8 μg/mL (Zhou et al. 2012). 1-(10-aminodecyl) pyridinium salt antibiotic (294) was purified from Amycolatopsis alba var. nov. DVR D4, which demonstrated inhibitory activity against Gram-positive and Gram-negative bacteria with MIC values ranging from 70 to 160 μg/mL (Dasari et al. 2012). 3-[(6-Methylpyrazin-2-yl)methyl]-1H-indole (295) was obtained from Serinicoccus profundi sp. nov., which displayed weak antibacterial activity against S. aureus ATCC 25923 with an MIC value of 96 μg/mL (Yang et al. 2013). Glycerol 1-hydroxy-2,5-dimethyl benzoate (296) was isolated from Verrucosispora sp. MS100047, which exhibited inhibitory activity against MRSA with an MIC value of 12.5 μg/mL (Huang et al. 2016). Kribellosides A‒D (297‒300) were discovered from Kribbella sp. MI481–42F6 and they inhibited S. cerevisiae with MICs ranging from 3.12 to 100 μg/mL (Igarashi et al. 2017). 5,6-Dihydro-1,8-dihydroxy-3-methylbenz[a]anthracene-7,12-quinone (301) was separated from Actinomadura sp. DS-MS-114, which was active against S. aureus NBRC12732 with an inhibition zone diameter of 12.7 mm at 100 μg/mL (Kurata et al. 2017). Kendomycins B–D (302−304) obtained from Verrucosispora sp. SCSIO 07399 had a broad spectrum of antibacterial activity against S. aureus ATCC 29213, S. aureus 745524, MRSA shhs-A1, E. faecalis ATCC 29212, B. subtilis BS01 and B. thuringiensis BT01 with MIC values ranging from 0.5 to 8.0 μg/mL (Zhang et al. 2019b). Salinaphthoquinones A–D (305−308) were isolated from Salinispora arenicola BRA-213, they showed antibacterial activities against S. aureus and E. faecalis with MIC values ranging from 16 to 125 μg/mL (da Silva et al. 2019).

Fig. 11.

Structures of compounds 284–313

Antimicrobial compounds from other actinomycetes from other marine sources

Maduralide (309) was obtained from an unidentified marine bacterium of the order Actinomycetales, which displayed weak antibacterial activity against B. subtilis (Pathirana et al. 1991). Taromycin A (310) was isolated from Saccharomonospora sp. CNQ-490, which exhibited inhibitory activity against MRSA and Enterococcus faecalis 613D with MIC values ranging from 6 to 100 μM (Yamanaka et al. 2014). Pseudonocardia carboxydivorans M-227 afforded branimycins B (311) and C (312). They showed a broad spectrum of antibacterial activities (Braña et al. 2017b). Thermoactinoamide A (313) was discovered from Thermoactinomyces vulgaris ISCAR 2354 and was active against S. aureus ATCC 6538 with an MIC value of 35 μM (Teta et al. 2017).

Conclusion

According to the statistic results (Table 1, Fig. 12), the investigation of antimicrobial compounds from marine-derived actinomycetes could be dated back to 1976 when aplasmomycin A (52) was isolated from Streptomyces griseus SS-20 (Table 2) (Okami et al. 1976). Until the end of 2019, 313 new antimicrobial compounds derived from marine actinomycetes have been reported. Since 2016, more secondary metabolites have been isolated from marine actinomyces than ever before except 2007 and 2009.

Table 1.

Antimicrobial compounds isolated from marine actinomycetes (1976‒2019)

Compound	Producing strain	Environmental source	Bioactivity	Ref.
1–2	Streptomyces sp. Ni-80	Unidentified sponge, Urauchicove, Iriomote, Japan	Antifungal activity	Imamura et al.1993.
3–12	Streptomyces sp. HB202	Halichondria panicea sponge, Baltic Sea (Germany)	Antibacterial activity	Mitova et al.2008; Schneemann et al. 2010; Kunz et al. 2014.
13–15	Streptomyces sp. BCC45596	Xestospongia sp. sponge, Thailand	Antibacterial activity	Supong et al.2012.
16–19	Streptomyces sp. LHW52447	Phyllospongia foliascens sponge, Xisha Islands, South China Sea	Antibacterial activity	Jiao et al. 2018
20–23	Streptomyces sp. SCSGAA 0027	gorgonian coral Melitodes squamata,, the South China Sea.	Antibacterial activity	Nong et al. 2016
24	Streptomyces sp. M-207	coral Lophelia pertusa, submarine canyon	Antibacterial activity	Braña et al. 2017a
25	Streptomyces cyaneofuscatus M-169	gorgonian coral (Order Gorgonacea), Avilés submarine Canyon	Antibacterial activity	Rodríguez et al. 2018
26	Streptomyces sp. SCSIO 41399	Porites sp. coral, Wenchang, Hainan, C	Antibacterial activity	Cong et al 2019
27–28	Streptomyces hygroscopicus	Jellyfish Cassiopeia xamachana, Florida Keys	Antibacterial activity	Trischman et al. 1994
29	Streptomyces sp. 1053U.I.1a.3b	L. totopotens, Mactan Island, Cebu, Philippines	Antibacterial activity	Lin et al. 2014
30	Streptomyces sp. CNB091	a jellyfish (C. xamachana), Florida Keys	Antibacterial activity	Hassan, et al. 2015
31	Streptomyces seoulensis A01	marine prawn, Yellow Sea, in China	Antibacterial activity	Zhang et al.2018a
32–34	Streptomyces sp. # N1–78-1	Unidentified green algae, Rhode Island	Antibacterial activity	Socha et al 2006
35	Streptomyces sp. WR1L1S8	the brown marine algae Fucus sp., Bejaia coastline	Antibacterial activity	Djinni et al 2013
36	Streptomyces althioticus MSM3	Seaweed Ulva sp., Cantabrian Sea (Northeast Atlantic Ocean)	Antibacterial activity	Braña et al 2019
37–40	Streptomyces sp. HKI0576	mangrove tree Bruguiera gymnorrhiza	Antibacterial activity	Ding et al 2011a
41–48	Streptomyces sp. HKI0595	mangrove tree Kandelia candel, Xiamen, China	Antibacterial activity	Ding et al. 2011a; Ding et al. 2012
49	S. lusitanus XM52	Mangrove root, Fujian, China	Antibacterial activity	Han et al. 2012
50	Streptomyces sp. MA-12.	Myoporum root, Leizhou Peninsula	Antibacterial and antifungal activity	Ding et al 2013
51	Streptomyces sp. LC6	Leaves of Kandelia candel, Longhai, Fujian, China	Antibacterial activity	Zhang et al 2014
52–54	Streptomyces griseus SS-20	Shallow sea sediment, Sagami Bay	Antibacterial activity	Okami et al 1976; Sato al. 1978
55–56	S.tenjimariensis SS-939	sea mud sample, Tenjin-island, Sagami-Bay	Antibacterial activity	Okami et al 1979
57	Streptomyces sp. CNB-253	Sediment, Bodega Bay, CA	Antibacterial activity	Pathirana et al. 1992
58–59	Streptomyces sp. BD-26T(20)	Sediment, Hawaii	Antibacterial activity	Sitachitta et al.1996
60	Streptomyces sp. B 8300	Sediment, Gulf of Mexico	Antibacterial activity	Biabani et al. 1997
61	Streptomyces sp. CNB-689	Sediment, Christchurch, New Zealand	Antibacterial activity	Jiang et al 1997
62	Streptomyces sp. strain B 8251	Sediment, Gulf of Mexico	Antibacterial activity	Pusecker et al.1997
63–64	Streptomyces sp. M428	Sediment, Geomun island	Antifungal activity	Cho et al. 1999
65	StreptomycesMSTMA190	Sediment, Victorian	Antibacterial activity	Capon et al. 2000
66	Streptomyces sp. 1010	Sediment, Livingston	Antibacterial activity	Ivanova et al. 2001
67	Streptomyces sp. B7064	Sediment, Hawaii	Antibacterial activity	Asolkar et al 2002.
68	Streptomyces sp. BD21–2	Sediment,Kailua Beach, Oahu, Hawaii	Antibacterial and antifungal activity	Schumacher et al. 2003
69	S. nodosus NPS007994	Sediment, Scripps Canyons, La Jolla	Antibacterial activity	Manam et al. 2005
70–71	Streptomyces sp.CNQ-085	Sediment, San Diego, CA.	Antifungal activity	Asolkar et al. 2006
72	Streptomyces sp.QD518	Sediment, Jiaozhou Bay, China	Antibacterial activity	Wu et al. 2006
73	Streptomyces sp.B8000	Sediment, Gulf of Mexico	Antibacterial activity	Poumale et al. 2006
74–76	Streptomyces sp CNQ-418	Sediment, La Jolla, CA	Antibacterial activity	Hughes et al. 2008; Hughes et al. 2010
77	Streptomyces sp. MS239	Sediment, Tokushima, Japan.	Antibacterial activity	Motohashi K et al. 2008
78	Streptomyces sp. Merv8102	Sediment, Mediterranean Sea, Egypt	Antibacterial activity	El-Gendy et al. 2008
79	Streptomyces sp. 307–9	Sediment,Salt Cay, U.S. Virgin Islands	Antibacterial activity	Carlson et al. 2009
80	Streptomyces sp. CMB- M0406	Sediment, Heron island, Australai	Antifungal activity	Sugiyama et al. 2014
81–83	Streptomyces sp. CMB- M0423	Sediment Heron Island, Queensland	Antibacterial activity	Raju et al. 2012
84–85	S. antibioticus H74–18	Sediment, South China Sea	Antifungal activity	Xu et al. 2011
86–88	Streptomyces sp. CNS-575	Sediment, Figi island	Antibacterial activity	Sun et al. 2011
89	Streptomyces species B8112	Sediment, Gulf of Mexico	Antifungal activity	Shaaban et al. 2011
90	Streptomyces sp. SCSIO 01127	Sediment, South China Sea	Antibacterial activity	Niu et al. 2011
91–96	Streptomyces sp. CNH-189	marine sediments, retrieved off shore of Oceanside, California.	Antibacterial activity	Wilson et al. 2011; Ryu et al. 2019
97–98	Streptomyces sp. 211726	rhizosphere soil of Heritiera globose, Wenchang, China	Antifungal activity	Yuan et al. 2011
99	Streptomyces sp. CMB- M0392	Sediment, Heron Island, Queensland	Antibacterial activity	Raju et al. 2012
100	Streptomyces sp. CNQ343	Sediment, North Cat Cay, Bahamas	Antifungal activity	Kim et al. 2012
101	Streptomyces sp. LB173	Sediment, Baltic Sea, Germany	Antibacterial activity	Ohlendorf etal. 2012
102–105	Streptomyces sp. SCSIO 02999	Sediment, South China Sea	Antibacterial activity	Zhang et al.,2012
106	Streptomyces sp. CP13–10	Sediment, SanFrancisco Bay, CA	antifungal activity	Amagata et al. 2012
107–109	Streptomyces sp. RJA2961	Sediment, British Columbia coast	Antibacterial activity	Dalisay et al. 2013
110–112	S. antibioticus PTZ0016	Sediment, Unknown place	Antibacterial activity	Lian et al. 2013
113–115	S. niveus SCSIO 3406	Sediment, South China Sea	Antibacterial activity	Song et al., 2013
116	Streptomyces sp. MS100061	Sediment, South China Sea	Antibacterial activity	Chen et al. 2013
117–118	Streptomyces sp.CNQ-329	Sediment, San Diego, CA.	Antibacterial activity	Cheng et al. 2013
119–121	Streptomyces sp. SCSIO 10428	Sediment, Beihai, Guangxi, China	Antibacterial activity	Wu et al. al.,2013a
122	Streptomyces sp. CNH365	Sediment, Santa Barbara, CA	Antibacterial activity	Jang et al. 2013
123–124	Streptomyces sp. 7–145	Sediment, Heishijiao Bay, China,	Antibacterial activity	Wu et al. 2013b
125–126	Streptomyces sp. SNJ042	Sediment, jeju Island	Antibacterial activity	Um et al. 2013
127	Streptomyces sp. 12A35	Sediment, South China Sea	Antibacterial activity	Pan et al. 2013
128	Streptomyces sp. CMBM0244	Sediment, Molle Island, Queensland	Antibacterial activity	Raju et al.,2014
129–133	S . drozdowiczii SCSIO 10141	Sediment, South China Sea	Antibacterial activity	Zhou al.,2014
133	S . scopuliridis SCSIO ZJ46	Sediment, South China Sea	Antibacterial activity	Song et al. 2014
135–136	Streptomyces sp. 06CH80	Sediment, Chuuk, Federated States of Micronesia and Ieodo, Korea	Antibacterial activity	Mondol et al. 2014
137	Streptomyces sp. SNR69	tidal mudflat in Buan, Korea	Antibacterial activity	Moon et al. 2015
138–139	Streptomyces sp. CMB- M0150	sediment collected off the Sunshine Coast, Queensland, Australia	Antibacterial activity	Khalil et al. 2015
140–143	Streptomyces sp. SNM5	intertidal zone mudflat, Mohang, Korea	Antibacterial:142–143 antifungal activity: 140–141	Bae et al. 2015a and b
144–146	Streptomyces zhaozhouensis CA-185989	Sediment, Utonde, Equatorial Guinea.	Antibacterial:144–146 antifungal activity: 144–145	Lacret et al. 2015
147–148	S . rochei 06CM016	sediment sample, Kaş, Turkey	Antibacterial and antifungal activity	Aksoy et al. 2016
149	Streptomyces sp. 182SMLY 06CM016	Sediment, East China Sea	Antibacterial	Liang et al. 2016
150–151	Streptomyces sp. IMB094	marine sediment, Heishijiao Bay, Dalian, China.	Antibacterial activity:	Wang et al. 2017
152	Streptomyces chartreusis NA02069	marine sediment, Hainan Island, Dalian, China.	Antibacterial activity:	Yang et al. 2017
153–156	Streptomyces chartreusis XMA39	marine sediment, Xiamen Island, Fujian, China.	Antibacterial and antifungal activity	Jiang et al.2018
157–158	Streptomyces sp. ZZ745	marine sediment, Zhejiang, China.	Antibacterial activity	Zhang et al. 2018b
159–160	Streptomyces Pratensis NA-ZhouS1	Marine sediment, Zhoushan, China.	Antibacterial activity	Akhter et al. 2018
161	Streptomyces xinghaiensis SCSIO S15077	Marine sediment, South China Sea, China.	Antibacterial and antifungal activity	Zhang et al. 2018c
162	Streptomyces sp. ZZ446	coastal soil	Antibacterial and antifungal activity	Chen et al. 2018a
163–166	Streptomyces sp. IMB7– 145	Marine sediment, Daliang, China.	Antibacterial: 163 antifungal activity :163–166	Hu et al. 2018
167	Streptomyces mutabilis sp. MII	Marine sediment, Red Sea, Hurghada Coast	Antibacterial activity	Hamed et al. 2018a
168	S . varsoviensis HF-11225	Marine sediment, East Sea, Hurghada Coast	Antifungal activity	Chen et al. 2018b
169–171	Streptomyces sp. OPMA 1245	Marine sediment, Okinawa prefecture, Japan	Antibacterial activity	Hosoda et al. 2019
172–174	Streptomyces sp. ZZ820	coastal soil	Antibacterial activity	Yi et al. 2019
175–176	Streptomyces sp. G212	Sediment, Quang Binh- Vietnam	Antibacterial:176 Antifugal: 175	Cao et al. 2019
177–186	Streptomyces sp. ZZ741	marine mud, the coastal area of Jintang Island, Zhoushan, China	Antibacterial and Antifungal activity	Zhang et al. 2019a
187	Streptomyces atratus SCSIOZH16	sediment sample	Antibacterial activity	Sun et al. 2019
188–191	Streptomyces sp. B8652	Sediment, Laguna de Terminos, Gulf of Mexico	Antibacterial activity	Maskey et al. 2002; Maskey et al. 2004
192–195	Streptomyces caelestis	coastal water of the Red Sea, near Jeddah	Antibacterial activity	Liu et al. 2012
196	Streptomyces sp. TPU1236A	Seawater, Okinawa, Japan	Antibacterial activity	Bu et al. 2014
197–200	Streptomyces caniferus CA-271066	Unknown source	Antifugal activity	Pérez-Victoria et al. 2019
201–202	Micromonospora lomaivitiensis LL-37I366	ascidian	Antibacterial activity	He et al. 2001
203	Micromonospora sp. DPJ12	Didemnum proliferum Kott, Japan	Antibacterial activity	Charan et al. 2004
204	Micromonospora sp.WMMC-218	Ascidian, Florida	Antibacterial activity	Zhang et al. 2016a
205	Micromonospora carbonacea LS276	Sponge, Hainan, China	Antibacterial activity	Gong et al. 2018
206	Micromonospora sp. K310	sediment, Ghanaian	Antibacterial activity	Kyeremeh K et al. 2014
207–208	Micromonospora sp.5–297	sediment, Dalian, China	Antibacterial activity	Tan et al. 2016
209–210	Micromonospora sp. G019	sediment, Viet Nam	Antibacterial activity:209–210 Antifugal : 210	Thi et al. 2016a
211–214	Micromonospora sp. RJA4480	Marine sediment BarkleySound, British Columbia	Antibacterial activity	Williams et al. 2017
215–221	Micromonospora harpali SCSIO GJ089	marine sediment, South China Sea	Antibacterial activity	Gui et al. 2017
222–223	Micromonospora sp. CA-214671	Marine sediment, Canary Island	Antibacterial activity	Pérez-Bonilla et al. 2018
224	Micromonospora sp. L-13- ACM2–092	Unknown source	Antibacterial activity	Perez Baz et al. 1997
225	Nocardiopsis dassonvillei	sediment sample, island of Kauai, Hawaii.	Antibacterial activity	Schumacher et al. 2001
226	Nocardiopsis sp. TFS65– 07	sediment sample, Trondheim Fjord, Norway	Antibacterial activity	Engelhardt et al. 2010
227–229	Nocardiopsis dassonvillei HR10–5	marine sediment, Yellow River.	Antibacterial activity	Fu et al. 2011
230–231	Nocardiopsis sp. CNQ115	marine sediment, the coast of southern California	Antibacterial activity	Leutou et al. 2015
232–234	Nocardiopsis sp. SCSIO 10419	marine sediment, Xieyang Island, Beihai, Guangxi, China	Antibacterial activity	Zhang et al. 2016b
235	Nocardiopsis sp. G057	marine sediment, Cô Tô- Quảng Ninh in Vietnam	Antibacterial activity	Thi et al. 2016b
236	Nocardiopsis sp YIM M13066	marine sediment, Cô Tô- Quảng Ninh in Vietnam	Antibacterial activity	Sun et al. 2017
237	Nocardiopsis sp. CNQ-115	marine sediment, Southern California	Antibacterial activity	Leutou et al. 2018
238	Nocardiopsis sp. LGO5	Marine sediment, Helwan, Egypt	Antibacterial activity	Hamed et al. 2018b
239–241	Nocardiopsis sp. HB-J378	marine sponge Theonella sp.	Antibacterial activity	Xu et al. 2018
242	Micrococcus luteus	sponge Xestospongia sp., New Caledonia	Antibacterial activity	Bultel-Poncé et al. 1998
243	Micrococcus sp. EG45	Red Sea sponge Spheciospongia vagabunda	Antibacterial activity	Eltamany et al. 2014
244	Kocuria Palustris	Sponge, Florida Keys	Antibacterial activity	Martín et al. 2013
245	Kocuria Palustris	Sponge	Antibacterial activity	Takasaka et al. 2017
246–248	Saccharothrix espanaensis An 113	a marine mollusc the Great Bay, Sea of Japan, Russia	Antibacterial activity	Kalinovskaya et al. 2008
249	Salinispora arenicola CNR-647	ascidian Ecteinascidia turbinata, Sweetings Cay, Grand Bahama Island	Antibacterial activity	Asolkar et al. 2010
250–251	Solwaraspora sp. WMMB329	ascidian Trididemnum orbiculatum	Antibacterial activity	Ellis et al. 2014
252	Actinomadura sp. WMMB-499	ascidian Ecteinascidia turbinata	Antifungal activity	Wyche et al. 2014
253–254	Pseudonocardia sp HS7.	the cloacal aperture of sea cucumber Holothuria moebii.	Antibacterial activity	Ye et al. 2016
255	Actinomadura sp.	ascidian Ecteinascidia turbinata	Antibacterial activity	Wyche et al. 2017
256–257	Lechevalieria aerocolonigenes K10–0216	Mangrove, Iriomote island	Antibacterial and antifungal activity	Kimura et al. 2018
258	Lechevalieria aerocolonigenes K10–0216	brown seaweed Pelvetia canaliculata (Linnaeus), the rocks of Sonmiani Beach (Karachi, Pakistan)	Antibacterial activity	Uzair et al. 2018
259–261	Actinomadura sp. M045	Sediment, Jiaozhou Bay.	Antifugal :259–261 Antibacterial activity:261	Maskey et al. 2003
262	Verrucosispora sp. AB-18– 032	sediment	Antibacterial activity	Bister et al. 2004
263–267	Marinispora sp. CNQ-140	sediment, La Jolla, California	Antibacterial activity:263–266 Antifugal:263 and 267	Kwon et al. 2006; Kwon et al. 2009
268	Verrucosispora sp. AB-18– 032	Sediment, Sea of Japan	Antibacterial activity	Keller et al. 2007
269–271	Marinispora NPS008920	sediment, Cocos Lagoon, Guam	Antibacterial activity	Macherla et al. 2007
272–276	Marinispora sp. NPS12745	sediment, the coast of San Diego, California	Antibacterial activity	McArthur et al. 2008
277–278	Verrucosispora maris AB-18–032	sediment, Raune Fjord, Norway	Antibacterial activity	Fiedler et al. 2008
279	Salinispora arenicora YM23–082	sediment, Yap, Micronesia	Antibacterial activity	Matsuda et al. 2009
280	Salinispora arenicola	sediment, Palau	Antibacterial activity	Murphy et al. 2010
281–283	Pseudonocardia sp. SCSIO 01299	sediment, the South China Sea	Antibacterial activity	Li et al. 2011
284–292	Actinoalloteichus sp. NPS702	sediment, Usa Bay, Kochi Prefecture, Japan	Antifungal activity	Sato et al. 2012
293	Marinactinospora thermotolerans SCSIO 00652	sediment, the South China Sea	Antibacterial activity	Zhou et al. 2012
294	Amycolatopsis alba var. nov. DVR D4	sediments from, Bay of Bengal	Antibacterial activity	Dasari et al. 2012
295	Serinicoccus profundi sp. nov.	a deep-sea sediment, Indian Ocean	Antibacterial activity	Yang et al. 2013
296	Verrucosispora sp. MS100047	sediment, the South China Sea	Antibacterial activity	Huang et al. 2016
297–300	Kribbella sp. MI481–42F6	sediment, Japna	Antifungal activity	Igarashi et al. 2017
301	Actinomadura sp. DS-MS-114	sediment, Sagami Bay	Antibacterial activity	Kurata et al. 2017
302–304	Verrucosispora sp. SCSIO 07399	sediment, the South China Sea	Antibacterial activity	Zhang et al. 2019b
305–308	Salinispora arenicola BRA-213	sediment, St.Peter and St. Paul Archipelago, Brazil	Antibacterial activity	da Silva et al. 2019
309	unidentified marine bacterium of the order Actinomycetales	the shallow waters of Bodega Bay	Antibacterial activity	Pathirana et al. 1991
310	Saccharomonospora sp. CNQ-490	Unknown source	Antibacterial activity	Yamanaka et al. 2014
311–312	Pseudonocardia carboxydivorans M-227	deep seawater of the Aviles submarine Canyon	Antibacterial activity	Braña et al. 2017b
313	Thermoactinomyces vulgaris ISCAR 2354	coastal hot spring, Icelandic marine waters	Antibacterial activity	Teta et al. 2017

Fig. 12.

Annual numbers of antimicrobial compounds identified (1976‒2019)

Table 2.

The initial research on antimicrobial active compounds from actinomycetes

Fist Producing Strain	Environment source	Compound.	Time
Streptomyces griseus SS-20	shallow sea sediment, Sagami Bay	Aplasmomycin A	1976
Micromonospora sp. L-13-ACM2–09	Unknown source	Thiocoraline	1997
Nocardiopsis dassonvillei	sediment sample, island of Kauai, Hawaii	Kahakamide A	2001
Other actinomycetes (unidentified marine bacterium of the order Actinomycetales)	the shallow waters of Bodega Bay	Maduralide	1991

These new marine natural products from actinomycetes have different types of structural skeletons including nitrogen-containing compounds, sterols and terpenoids, polyketides, and others (Fig. 13). Polyketides and nitrogen-containing compounds (e.g., alkaloids and peptides) are the two main classes (Fig. 13). Because of high halogen concentrations in the Ocean when compared with that on Land, marine actinomyces produced more halogen-containing compounds than their terrestrial counterparts. None of the terpenoids and steroids among the 313 compounds cited in this review article showed potent antimicrobial activity when compared with the other classes of compounds. Compounds 74 and 76, halogenated alkaloids each with two pyrrolphenone moieties inhibited MRSA with an MIC value less than 1 μg/mL (Hughes et al. 2008 and Hughes et al. 2010). Compounds 201, 202 and 211‒214 are polyketides-derived 1,4-naphthoquinone alkaloids. Compounds 201 and 202 inhibited S. aureus and E. faecium with MIC values ranging from 6 to 25 ng/spot (He et al. 2001). Compounds 211‒214 inhibited MRSA, E.coli and M. tuberculosis with MIC values in the range of 0.3–0.9, 0.1–0.8, and 60–1800 ng/mL, respectively (Williams et al. 2017). Compounds 16‒19 are bicyclic nitrogen-containing compounds each with a phenoxazine bridge. One cyclic peptide fragment (threonine-valine-proline-glycine-valine) was connected to one aromatic ring through an amide bond, and another cyclic peptide fragment (threonine-valine-proline-glycine-valine) was connected to another aromatic ring also through an amide bond. Compounds 16‒19 inhibited MRSA with MIC values less than 1.0 μg/mL (Jiao et al. 2018). Compound 128, a cyclic peptide, exhibited potent antibacterial activity at nanomolar concentrations (Raju et al. 2014). Cyclic peptides 129‒133 inhibited M. luteus with MIC values in the range of 0.061–4.00 μg/mL (Zhou et al. 2014). Compounds 169‒171 are cyclic peptides with some nonstandard amino acids (169 and 171) or hybrids of polyketide and peptide (170). Compounds169 and 171 strongly inhibited M. avium JCM15430, M. intracellulare JCM6384 and M. bovis BCG Pasteur with MIC values in the range of 12 to 780 ng/mL (Hosoda et al. 2019). Besides 170 (hybrids of polyketide and peptide), 201, 202 and 211‒214 (1,4-naphthoquinone alkaloids derived from polyketides), some other polyketides (for examples, 25, 32‒34, 122, 255, and 263‒266) also demonstrated potent antimicrobial activity. Compounds 32‒34 are polyketide anthraquinone derivatives, among which compounds 32 and 33 inhibited MRSA with IC₅₀ values of 0.15 and 0.36 μM, respectively (Socha et al. 2006). Compound 255 is a polyketide derived polyether. It inhibited MRSA, MSSA and C. difficile with MIC values in the range of 59‒125 ng/mL (Wyche et al. 2017). The macrolides 263‒266 are polyketide polyenes, and they inhibited MRSA with MIC₉₀ values in the range of 0.13‒0.25 μM. Other two macrolides 25 (Rodríguez et al. 2018) and 122 (Jang et al. 2013) also exhibited antibacterial activity at ng/mL level. Glycosylated macrolides 135 and 136 inhibited B. subtilis, E. coli, P. aeruginosa, S. aureus and S. cerevisiae with MIC values in the range of 0.027 to 0.22 μM (Mondol et al. 2014).

Fig. 13.

Structural classes of antimicrobial compounds isolated from marine actinomycetes (1976‒2019)

Marine actinomycetes are efficient producers of new secondary metabolites. The numbers of antimicrobial compounds from marine Streptomyces sp., Micromonospora sp., Nocardiopsis sp. and the other actinomycetes except Streptomyces sp., Micromonospora sp., and Nocardiopsis sp. were 200, 24, 17 and 72, respectively (Fig. 14), among which about 64% were produced by Streptomyces sp. Other actinomycetes (for examples, Micromonospora, Nocardiopsis, Salinispora and Pseudonocardia) are also prolific producers of secondary metabolites in the marine environment. The numbers of antibacterial and anti-fungal compounds identified from marine actinomycetes are 272 and 70, respectively (Fig. 15).

Fig. 14.

Numbers of antimicrobial compounds from different marine actinomycetes (1976‒2019)

Fig. 15.

Numbers of antibacterial and anti-fungal compounds from marine actinomycetes (1976‒2019)

Scholars in Europe and America, China and other Asian countries published 145, 106 and 50 antimicrobial compounds, respectively (Fig. 16). Different from the antimicrobial study of marine fungi in which Chinese scientists are the most productive in recent years, researchers in Europe and America published 156 antimicrobial compounds from marine actinomycetes, slightly more than scholars in Asia who reported 145 antimicrobial compounds.

Fig. 16.

Numbers of antimicrobial marine metabolites by different countries (1976‒2019)

J. Nat. Prod. attracted the most contributions (32 articles), followed by J. Antibiot. (27 articles) and Mar. Drugs (23 articles), which accounts for 83% (= 82/99) of all the published papers (Fig. 17). Nearly one-third (31.6%) of all the new antimicrobial compounds were pubished in J. Nat. Prod. followed by Mar. Drugs (12.2%) and by J. Antibiot. (12.1%) (Fig. 18). The dominant host of actinomycetes was marine sediment with a ratio of 69.6% (Fig. 19). Marine animals were also good hosts for actinomycetes (16.9%). Rare marine actinomycetes (for example, Salinispora sp. from deep-sea sediments) in combination of new screening approach will provide more antimicrobial agents.

Fig. 17.

Journals and numbers of papers that published antimicrobial compounds (1976‒2019)

Fig. 18.

Percentages of antimicrobial compounds published in different journals (1976‒2019)

Fig. 19.

Percentages of antimicrobial compounds on the basis of the hosts of actinomycetes (1976‒2019)