Progress in Microbes and Molecular Biology Review Article 1 A Review on Mangrove Actinobacterial Diversity: The Roles of Streptomyces and Novel Species Discovery Jodi Woan-Fei Law1,2, Priyia Pusparajah1, Nurul-Syakima Ab Mutalib3, Sunny Hei Wong4, Bey-Hing Goh5*, Learn-Han Lee1* 1Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor Darul Ehsan, Malaysia 2Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China 3UKM Medical Molecular Biology Institute (UMBI), UKM Medical Centre, University Kebangsaan Malaysia, Kuala Lum- pur, Malaysia 4Li Ka Shing Institute of Health Sciences, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong 5Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Selangor Darul Ehsan, Malaysia Abstract : In the class Actinobacteria, the renowned genus Streptomyces comprised of a group of uniquely complex bacteria that capable of synthesizing a great variety of bioactive metabolites. Streptomycetes are noted to possess several special qual- ities such as multicellular life cycle and large linearized chromosomes. The significant contribution of Streptomyces in mi- crobial drug discovery as witnessed through the discovery of many important antibiotic drugs has undeniably encourage the exploration of these bacteria from different environments, especially the mangrove environments. This review emphasizes on the genus Streptomyces and reports on the diversity of actinobacterial population from mangroves at different regions of the world as well as discovery of mangrove-derived novel Streptomyces species. Overall, the research on diversity of Actinobac- teria in the mangrove environments remains limited. A total of 19 novel Streptomyces spp. isolated from mangroves between the year 2009 - early 2019, notably from China, India, Malaysia, and Thailand. Hence, it will be worthwhile to encourage the study of these bacteria from mangroves of different locations. Keywords: Streptomyces; actinobacteria; mangrove; environment; forest Received: 06th January 2019 Accepted: 30th April 2019 Published Online: 22nd May 2019 *Correspondence to: Learn-Han Lee, Jeffrey Cheah School of Medicine and Health Sciences, Monash Uni- versity Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. lee.learn.han@monash.edu; leelear- nhan@yahoo.com; Bey-Hing Goh, School of Pharma- cy, Monash University Malaysia, 47500 Bandar Sun- way, Selangor Darul Ehsan, Malaysia. goh.bey.hing@ monash.edu Citation: Law JWF, Pusparajah P, Ab Mutalib NS, et al. A Review on Mangrove Actinobacterial Diversity: The Roles of Streptomyces and Novel Species Discovery. Prog Microbes Mol Biol 2019; 2(1): a0000024. INTRODUCTION The phylum Actinobacteria is among the earliest lineages within the prokaryotes which appears to exist since 2.7 billion years ago[1]. Being one of the major lineages in the domain Bacteria, this phylum consists of many genera which contributed to its vast diversity with reference to the morphological and physiological variations as well as metabolic abilities[2-4]. In the recent road map of phy- lum Actinobacteria revised by Ludwig et al. (2012)[5], this phylum currently comprises 6 classes, namely “Ac- tinobacteria”, “Nitriliruptoria”, “Acidimicrobiia”, “Co- riobacteriia”, “Thermoleophilia”, and “Rubrobacteria”. The largest class “Actinobacteria” consists of 15 orders, including order Streptomycetales that contains only the family Streptomycetaceae, where the type genus Strep- tomyces within this family is undeniably one of the most extensively studied genera in the phylum Actinobacte- ria[5-7]. The class Actinobacteria can be categorized into two groups: (1) the Streptomyces which represents the dominant genus, and (2) the non-Streptomyces genera (e.g. Sinomonas spp., Mumia spp., Microbacterium spp. etc.) which also known as rare Actinobacteria[8-13]. The genus Streptomyces was first introduced by Profes- sor Dr. Selman Abraham Waksman and Professor Dr. Arthur Trautwein Henrici in the year 1943[14]. The name Streptomyces means “twisted fungus” in Greek and it is given due to its morphology which appears to be simi- Copyright 2019 by Law JWF et al. and HH Publisher. This work under licensed under the Creative Commons Attribution-NonCom- mercial 4.0 International Lisence (CC-BY-NC 4.0) 2 lar to that of filamentous fungi; Streptomyces is derived from the combination of Actinomyces which means “ray fungus” in Greek and Streptothrix which means “twisted hair” in Greek[14,15]. This genus is made up of a group of aerobic, Gram-positive, non-motile, and multicellular filamentous microorganisms that are commonly found in soil, often recognized as persistent soil saprophytes[16-19]. Besides, most of the members of Streptomyces produce a characteristic earthy odour due to the production of geos- min[7,20]. This group of bacteria has been greatly explored for their pharmaceutically important natural antibiotics or other bioactive compounds, and industrially useful en- zymes[1,17,21]. As a result of the continuous efforts in isola- tion and screening of Streptomyces for their biologically active secondary metabolites, the genus Streptomyces presently contains 848 species and 38 subspecies that are validly identified (http://www.bacterio.net/streptomyces. html, accessed on 15th January 2019)[22]. UNIQUE FEATURES OF Streptomyces Streptomyces bacteria are uniquely complex microor- ganisms, primarily well-known as prolific producers of secondary metabolites with bioactivities such as antimi- crobial, anticancer, antioxidant, and immunosuppressive activities[19,20,23,24]. Production of secondary metabolites is not essential for bacterial growth, but it is crucial to facilitate the defence mechanisms of the hosts as to en- sure survival during unfavourable environmental condi- tions[6]. It is remarkable that streptomycetes can generate secondary metabolites with various interesting bioactivi- ties and extraordinary chemical diversity, although the roles play by these molecules in the survival of the host are still not fully understood other than the antibiotics which benefit the host by thwarting the growth of com- peting microbes in unfavourable environment[18,25]. Actually, there are several notable features of Strepto- myces that could account for their complex secondary metabolism. One of the unique features of streptomy- cetes is their multicellular life cycle involving com- plex morphological changes. Upon spore germination, they grow by tip extension and the development of a network of branched filaments known as the substrate mycelium (vegetative phase) is initiated. As they age, aerial multinucleated mycelium is formed which sub- sequently experience synchronous cell division leading to the generation of monoploid compartments where each will differentiate into resistant spores (reproductive sporulation phase) (Figure 1)[18,26,27]. According to the ob- servation on agar plate media, the substrate mycelium of Streptomyces grows into and across the surface of agar plate through extension and branching, whilst the aerial mycelium erected on top of the substrate mycelium that appears above the surface of agar plate with granular, powdery, floccose or velvety appearance[26,28]. Apparently, the morphological differentiation event in Streptomyces is related to the sensing of essential nutrients depletion[18,27]. Meanwhile, Streptomyces starts to produce secondary metabolites when encountering nutritional deficiencies in a stressful environment and this process is referred to physiological differentiation[29]. Therefore, there is a close association between morphological differentia- tion and physiological differentiation in the life cycle of Streptomyces. During the shifting phase from vegetative to aerial growth and sporulation, metabolic development is activated and thus many interesting secondary metabo- lites are produced to ensure the survival of Streptomyces in stressful environments[27,29,30]. Furthermore, many of the Streptomyces isolates can produce diverse pigments or pigmented secondary metabolites that responsible for the colour of substrate and aerial mycelia of Streptomyces colonies on agar plate media[26,30]. Another distinctive feature of Streptomyces is that mem- bers of this genus have linearized chromosomes, com- monly with a large size of over 8 Mbp and a high G+C content of approximately 67-78 mol %[32-34]. In the year 2002, the first complete genome sequence of Streptomy- ces was reported - a model actinomycete, Streptomyces coelicolor A3(2) with a genome size of 8,667,507 bp, thus, became the largest completely sequenced bacterial genome at that moment[35]. In the following year, the com- plete genome sequence of an industrial strain Streptomy- ces avermitilis was reported to consist of 9,025,608 bp[36]. Since then, many Streptomyces strains have been subject- ed to whole genome sequencing to at least the draft stage and these genome sequences are publicly available[37]. These evidences show that the genome size of Streptomy- ces is at least almost two times larger as compared with other well-studied bacteria such as Bacillus subtilis with genome size of 4,214,810 bp, and Escherichia coli K-12 with genome size of 4,639,221 bp[20,38,39]. The large ge- nome size correlates with the ability of Streptomyces to produce large amount of diversified secondary metabo- A Review on Mangrove Actinobacterial... Figure 1. Schematic representation of the life cycle of Streptomyces (adapted from Barka et al. (2016)[31]). 3 lites. For instance, Bentley et al. (2002)[35] reported that the genome of Streptomyces coelicolor A3(2) was found to contain over 20 gene clusters related to/involved in the biosynthesis of secondary metabolites. Besides, Ikeda et al. (2003)[36] noted the presence of over 30 biosynthetic gene clusters Streptomyces avermitilis associated to various sec- ondary metabolites. Therefore, these special features of Streptomyces have contributed to the complexity of the or- ganisms, causing them to be capable of producing a vast ar- ray of interesting or novel bioactive secondary metabolite. ROLES OF Streptomyces IN MICROBIAL DRUG DISCOVERY The search for antibacterial agents from Streptomyces had in fact began since the early 1940s, before the reclassifica- tion of Actinobacteria and the introduction of genus Strep- tomyces. Pioneered by Professor Dr. Selman A. Waksman, who ventured into the discovery of antagonistic soil-inhab- iting microbes towards pathogenic bacteria with his team of scientists[40]. The outcome of their investigation led to the isolation of first antibiotic designated as actinomycin, a specific bacteriostatic and bactericidal agent, produced by Streptomyces antibioticus (formerly known as Actinomy- ces antibioticus)[20,41,42]. A few years later, Waksman and his team achieved a breakthrough in Streptomyces research, which was the discovery of streptomycin as a cure for many diseases[40,43]. Streptomycin was the first discovered broad-spectrum antibiotic for effective treatment of tuber- culosis caused by Mycobacterium tuberculosis – a deadly pathogen. Streptomycin was derived from Streptomyces griseus, the first Streptomyces to be utilized for industrial production of this antituberculosis drug[1,25,40,43,44]. From this event, Professor Selman A. Waksman was awarded with the Nobel Prize in Physiology or Medicine in 1952 for his successful discovery of streptomycin[6]. Eventually, scientists intensified the search for antibiot- ics from Streptomyces. Consequently, Streptomyces has become the producers of over 75% of the commercially valuable antibiotics applied in human and veterinary medi- cines[45]. A variety of antibiotics belonging to different classes can be sourced from Streptomyces, for instances: clavulanic acid (class: β-lactam) from Streptomyces clavu- ligerus[46], neomycin (class: aminoglycoside) from Strepto- myces fradiae[47], vancomycin (class: glycopeptide) from Streptomyces orientalis[48], and tetracycline (class: tetracy- cline) from Streptomyces aureofaciens[49]. After a period of more than 50 years since the amazing achievement of Professor Selman A. Waksman, streptomy- cetes continue to surprise the scientific community by their ability in synthesizing functionally and structurally varied bioactive compounds. These bacteria have relentlessly showcasing their significance in the drug discovery and de- velopment. Recently, Professor Satoshi Omura and Profes- sor William Cecil Campbell were bestowed with the Nobel Prize of Physiology or Medicine in 2015 for the successful discovery of avermectin (which later chemically modified to ivermectin) from Streptomyces avermitilis. Avermectin is a strong anthelmintic agent effective against many nem- atodes, arachnids, and insects. The semisynthetic deriva- tive ivermectin is an effective treatment for onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) in human[50-52]. To date, researchers are still actively searching for bioactive Streptomyces strains around the world due to their enormous potential in producing effective drug candidates and many efforts have been put to further ex- plore the potential of these organisms in producing other clinically important compounds (examples: anticancer, antioxidant etc.) in addition to antibiotic agents[53]. OCCURRENCE OF Streptomyces FROM DIF- FERENT HABITATS Terrestrial and aquatic environments Member of Streptomyces are ubiquitous in soil and aquatic sediments, existing either in a metabolically active state or relatively inactive state in the form of spores. Streptomyces is among the significant micro- bial populations in most terrestrial soils, thus, the soil is the most extensively studied habitat as a rich source of streptomycetes[54]. Additionally, streptomycetes have a substantial role in soil ecology through their involve- ment in biodegradation. These organisms are capable of degrading recalcitrant polymers present in soil and plant litter, such as lignocelluloses, chitin, and keratin[54,55]. Soil-derived streptomycetes have been the producers of pharmaceutically important bioactive compounds and valuable enzymes. Therefore, Streptomyces of terres- trial soil origin has been greatly exploited in many drug screening programs for the past decades. Moreover, it is common to find Streptomyces in marine environments where they were frequently assumed to be derived from spores that wash-in from adjacent terrestrial habitats[54]. Nevertheless, several studies have proven the existence of indigenous marine Streptomyces, although their distributions and ecological roles remain elusive[56-59]. There are also evidences for the presence of Strepto- myces in other aquatic environments such as freshwater lakes and rivers[54,60,61]. Living organisms Furthermore, some streptomycetes exist as symbionts instead of free-living soil bacteria. They create a sym- biotic relationship with other organisms such as plants and invertebrates, whereby these interactions can either be beneficial or parasitic in some cases[62]. Streptomyce- tes that associated with plants could lead a pathogenic or endophytic lifestyle. While the presence of phyto- pathogenic Streptomyces species are scarce, but one of the most notable phytopathogenic streptomycetes is Streptomyces scabies. Streptomyces scabies is the pri- mary causative agent of common scab disease in potato and other crops including beet and radish[63]. As for en- dophytic Streptomyces species, they could live as plant commensals whilst occasionally provide certain ben- eficial properties to their hosts such as protection from phytopathogens or plant growth promotion. Also, stud- ies have demonstrated that endophytic streptomycetes could be attractive biocontrol agents due to their ability in generating antibacterial or antifungal agent that can eradicate phytopathogens [19,62,64]. There are several Streptomyces species have been found to form protective mutualistic symbioses with insects such as European beewolf, Southern pine beetles, and attine ants, in which basically the Streptomyces offers Law JWF et al. 4 protection to its host or host’s resources against pathogens through the production of antibiotics, in return, the host feeds the Streptomyces[62,65-67]. Apart from forming symbio- ses with insects, many reports have revealed the associa- tions between Streptomyces species and marine sponges as well as cone snails though the symbiotic relationships be- tween these organisms remain inconclusive as further stud- ies are required to address these queries[62,68,69]. Other unique environments Interestingly, Streptomyces bacteria happen to be widely distributed in extreme and underexplored environments such as deserts[70], caves[71], hot springs[72], mangroves[33,73], mountain plantations[55], Arctic and Antarctic regions[74,75]. These environments are often characterized by certain fluc- tuations in environmental conditions, extreme high/low temperature, acidic/alkaline pH, limitation of nutrients, or high radiation[1]. Existence of Streptomyces in these unusu- al environments have demolished the traditional paradigm pertaining the restricted predominance of Streptomyces in terrestrial soil and aquatic environments. It is relatively unsurprising that streptomycetes can occur in these envi- ronments because they can exist for an extended period as resting arthrospores; these spores are resistant to wa- ter and high temperatures, also, they will germinate when sufficient nutrients are available[16,54]. These bacteria also possess physiological and metabolic flexibility that could trigger the production of secondary metabolites to facilitate their survival under extreme conditions[1,74]. EXPLORATION OF Streptomyces FROM UN- DEREXPLORED MANGROVE Recent drug discovery research seeks to discover novel and useful bioactive compounds by emphasizing on the screen- ing of Streptomyces species from uncommon and underex- plored areas. There is increasing evidence that bioprospect- ing of Streptomyces from dynamic environment like the mangroves are producing positive outcomes[6]. Similarly, mangroves have been regarded as one of the rich resources for isolating Streptomyces bacteria, which also includes novel Streptomyces species[76]. There has been increasing number of mangrove-derived Streptomyces strains exhibit- ing potent bioactivities such as antimicrobial, anticancer, and antioxidant[20,77-81]. It is possible that mangrove strep- tomycetes have unique metabolic capacity on the synthesis of bioactive secondary metabolites. Therefore, it is worth- while to pursue new groups of Streptomyces from less in- vestigated ecological systems such as the mangroves in hopes to unearth novel and/or useful bioactive compounds from these organisms. The mangrove environment The mangroves stand out as an exceptional type of forest distributed along the intertidal zone between the terrestrial and the sea of tropical and subtropical regions around the world[82]. Mangroves are described as assemblage of trees and shrubs adapted to thrive in dynamic environmental set- tings of extreme tides, high salinity, high temperature, and high sedimentation[82,83]. Despite those harsh environmental conditions, these “rainforests of the seas” are very produc- tive and biologically significant ecosystems, for which they provide a superb nursery habitat for a wide range of flora and fauna[84]. Of course, mangrove forests offer invalu- able benefits towards human society besides sustaining biodiversity. These wetland forests provide ecosystem goods that are vital to sustain human well-being, which cover food source (e.g. fish, shrimps), boat building ma- terials, furniture, firewood, and traditional medicine[85]. Mangrove forests also provide protection by buffering salinity changes, stabilizing shorelines through reducing coastal erosion, and minimizing severe impact of natural disasters like floods, tidal waves, hurricanes, and tsuna- mis[82,86,87]. The latest update on global distribution of mangroves was reported in the 2010 World Atlas of Mangroves, with the inputs from several organizations including the International Tropical Timber Organization (ITTO), In- ternational Society for Mangrove Ecosystems (ISME), Food and Agriculture Organization (FAO), United Na- tions Environment Programme (UNEP), and others. It was estimated that the mangrove area was a total of 152,361 km2 found in 123 countries and territories, based on satellite imagery captured in year 1999 – 2003[88,89]. The distribution of mangroves in each region is sum- marized in the chart illustrated in Figure 2. The larg- est proportion of mangroves is found in Southeast Asia, where Indonesia, Malaysia, and Myanmar are the top three mangrove-rich countries within this region[82,89]. BACTERIAL DIVERSITY OF MANGROVE Mangroves have a highly diverse microbial communi- ty comprising numerous different species of fungi and bacteria. In the mangrove sediments, bacteria are the primary decomposers of organic residues and the main contributors in the carbon cycle. Many of them are asso- ciated with ecologically important roles such as nitrogen fixation, phosphate solubilising, sulphate reducing, en- zyme producing, photosynthetic anoxygenic, and meth- anogenic[90,91]. Based on previous research findings, the bacterial assemblages which dominated the mangrove ecosystems include phyla Proteobacteria, Actinobacte- ria, Firmicutes, Bacteroidetes, Chloroflexi, Acidobac- teria, Cyanobacteria, Nitrospirae, Fusobacteria, and Planctomycetes[92-96]. Given the fact that bacteria control the nutrient availabil- ity in the environment, so the abundance of these bac- teria present in mangroves could result in an increased amount of nutrient levels in the sediments, thereby controlling vegetation patterns, stimulating growth of many organisms, and promoting species diversity[91,97,98]. Above all, the periodic tidal flushing and constant fluc- tuation in salinity could induce changes in metabolic pathways in microorganisms for their adaptation to the mangrove environment. Henceforth, these factors could encourage the advent of “new” species that have the po- tential to produce uncommon metabolites which may be compelling to the pharmaceutical and biotechnology industry[45,94,99]. Diversity of Actinobacteria in mangrove Actinobacteria are important soil inhabitants and the exploration of Actinobacteria in mangroves has been gaining attention from researchers around the world due A Review on Mangrove Actinobacterial... 5 to their incredible contribution to drug discovery. In the recent years, there are several reports regarding the diver- sity of Actinobacteria in mangroves, mainly from the East Asia, South Asia, and Southeast Asia regions. The Actinobacteria population in mangrove forests of China of East Asia region was investigated by Hong et al. (2009)[100]. In the report, more than 2,000 actinomycetes were isolated from soil and plant samples obtained from eight mangrove sites. Furthermore, many of these acti- nomycetes exhibited biological activities such as growth inhibition of Human Colon Tumor 116 cells, antimicro- bial activity against Candida albicans and Staphylococ- cus aureus, inhibition of protein tyrosine phosphatase 1B (PTP1B), caspase 3 and aurora kinase A. It was found that the bioactive strains were belonged to 13 genera and most of them were from the genus Streptomyces (Table 1). The study also revealed that most of the bioactive actino- mycetes were originated from soil samples. On the other hand, a study conducted by Wei et al. (2010)[101] demon- strated that 77 out of 118 actinobacterial strains isolated from China mangrove plant samples exhibited antibiotic property and these bioactive strains were from the genus Streptomyces, Micromonospora, Nocardia, Nocardiopsis, Saccharothrix, and Lentzea. In the South Asia region, one of the largest areas of man- groves is situated in India. A few researchers have reported the actinobacterial diversity in India’s mangroves. For in- stance, the distribution of Actinobacteria in mangrove for- ests of Sundarbans in India was examined by Mitra et al. (2008)[102] and the actinomycetes isolated from soil samples were found to belonged to 9 genera with potential antimi- crobial activity. In addition, Rajkumar et al. (2012)[76] had unveiled the isolation of 116 actinomycetes belonging to 7 genera from sediment samples collected from five sites of Bhitarkanika mangroves (Table 1). These studies have showed that Streptomyces emerged as the most prevalent genus detected in the mangroves of India[76, 102]. As for the Southeast Asia region, Lee et al. (2014)[45] dis- covered a high level of diversity of Actinobacteria in man- grove forest located at Peninsular Malaysia. A total of 87 actinobacterial isolates from mangrove soil samples were identified to belong to 11 genera and 48 of these isolates exerted antibacterial activity to at least 1 of the 12 patho- gens tested, which were Bacillus subtilis, Bacillus cereus, Enterococcus faecalis, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, Klebsi- ella pneumonia, Klebsiella oxytoca, Salmonella typhi, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Yersinia pseudotuberculosis, and Aeromonas hydroph- ila. Additionally, diversity of Actinobacteria in man- grove soil of Indonesia was reported by Retnowati et al. (2017)[103], for which they had revealed mangrove acti- nomycetes with antibacterial activity belonging to the genus Amycolatopsis, Nocardiopsis, Streptomyces, and Saccharomonospora. The studies on the actinobacterial population in mangroves of different locations are sum- marized and listed in Table 1. Among the many genera of class Actinobacteria, there is no doubt that the genus Streptomyces is the most bio- logically active microorganisms. As a result, the explo- ration of Streptomyces in mangrove environments has been the centre of attraction, which subsequently lead to the discovery of novel species. Table 2 describes the discoveries of novel Streptomyces species isolated from several mangrove areas. Meanwhile, there are some studies focusing on the di- versity of only the rare Actinobacteria. The rare Acti- nobacteria are recognized as non-Streptomyces strains of actinomycetes and the frequency of isolation of these actinomycetes through conventional methods is often lower as compared to that of Streptomyces[108,109]. One of the examples include the study conducted by Naik- patil et al. (2011)[110] who investigated the rare Actino- bacteria from mangrove sediments of Karwar, India. A total of 53 rare actinomycetes were isolated in the study and identified as Actinoplanes, Actinomadura, Micro- bispora, and Micromonospora. Another research led by Ismet et al. (2013)[111] described the diversity of rare actinomycetes in mangrove rhizosphere soil samples collected from several mangrove sites in Bangladesh. Rare actinomycetes belonging to Actinomadura, Actino- planes, Catellatospora, Longispora, Micromonospora, Microbispora, Nocardia, Nocardiopsis, Nonomuraea, Rhodococcus/Gordonia, Saccharomonospora, Strepto- sporangium, and Virgisporangium were isolated from the soil samples. Figure 2. The global distribution of mangrove (information obtained from ITTO (2012))[89]. Law JWF et al. 6 A Review on Mangrove Actinobacterial... Region Author Country Mangrove location Source Diversity of Actinobacteria East Asia Hong et al. (2009)[100] China i. Hainan Province: Dan- zhou, Haikou, Sanya and Wenchang ii. Guangdong Province: Shenzen and Zhanjiang iii. Fujian Province: Xiameng iv. Guangxi Province: Beihai Soil and plant samples Actinoplanes, Actinomadura, Arthrobacter, Isoptericola, Microbacterium, Microbispora, Micrococcus, Micromonospora, Nocardia, Nonomuraea, Rhodococcus, Streptomyces, and Verrucosispora. Wei et al. (2010)[101] China Guangxi Province: Shankou Mangrove Nature Reserve Plant samples Lentzea, Micromonospora, Nocardia, Nocar- diopsis, Saccharothrix, and Streptomyces. Liao et al. (2010)[104] China Guangxi Province: Beihai Soil samples Streptomyces and Nocardiopsis. Jiang et al. (2018)[105] China Guangxi Zhuang Autono- mous Region: Beilun Es- tuary National Nature Re- serve Plant samples Actinoplanes, Agrococcus, Amnibacterium, Brachybacterium, Brevibacterium, Citricoc- cus, Curtobacterium, Dermacoccus, Glu- tamicibacter, Gordonia, Isoptericola, Jani- bacter, Kineococcus, Kocuria, Kytococcus, Leucobacter, Marmoricola, Microbacterium, Micrococcus, Micromonospora, Mycobacte- rium, Nocardia, Nocardioides, Nocardiopsis, Pseudokineococcus, Sanguibacter, Strepto- myces, and Verrucosispora. South Asia Mitra et al. (2008)[102] India Indian Sundarbans: i. Bally jetty ii. Pakhiralaya 1 iii. Pakhiralaya 2 iv. Jamespore v. Dattar forest vi. Bally forest Soil samples Actinomadura, Actinoplanes, Nocardia, No- cardiopsis, Micromonospora, Saccharopolys- pora, Streptomyces, Streptosporangium, and Streptoverticillium. Rajkumar et al. (2012)[76] India Sites of Bhitherkanika: i. Kola creek ii. Bhiterkkanika iii. Baguludia iv. Kalibhanchidia v. Thanidia Sediment sam- ples Actinomadura, Actinomyces, Actinopolyspo- ra, Micromonospora, Nocardiopsis, Saccha- ropolyspora, and Streptomyces. Karthikeyan et al. (2013) [106] India Tamil Nadu: Ennoor Soil samples Actinokineospora, Actinopolyspora, Amyco- lata, Glycomyces, Microbispora, Microtet- raspora, Micropolyspora, Nocardia, Nocar- diopsis, Promicromonospora, Saccharothrix, Saccharopolyspora, Streptomyces, Strepto- verticillium, Spirillospora, and Thermomono- spora. Southeast Asia Lee et al. (2014)[45] Malaysia Pahang: Tanjung Lumpur Soil samples Gordonia, Leifsonia, Microbacterium, Mi- cromonospora, Mycobacterium, Nocardia, Nocardioides, Sinomonas, Streptacidiphilus, Streptomyces, and Terrabacter. Malek et al. (2015)[107] Malaysia Pahang: Tanjung Lumpur Soil samples Actinophytocola, Gordonia, Micromonospo- ra, Mycobacterium, Pseudonocardia, Rhodo- coccus, and Streptomyces. Retnowati et al. (2017)[103] Indonesia Gorontalo Province: Toro- siaje Soil samples Amycolatopsis, Nocardiopsis, Streptomyces, and Saccharomonospora. Table 1. Actinobacterial diversity present in mangroves at East Asia, South Asia, and Southeast Asia regions. 7 No. Strain name and designation Mangrove sampling site Source Reference 1. Streptomyces avicenniae MCCC 1A01535T National mangrove reserve in Fujian Province, China Rhizosphere of mangrove plant Avicennia mariana Xiao et al. (2009)[112] 2. Streptomyces xiamenensis MCCC 1A01550T National mangrove reserve in Fujian Province, China Sediment Xu et al. (2009)[113] 3. Streptomyces sundarbansensis MS1/7T Sundarbans mangrove forest, India Sediment Arumugam et al. (2011)[114] 4. Streptomyces shenzhenensis 172115T Shenzhen, China Sediment Hu et al. (2011)[115] 5. Streptomyces sanyensis 219820T Sanya, Hainan Province, China Composite sediment Sui et al. (2011)[116] 6. Streptomyces qinglanensis 172205T Qinglan Harbour, Wenchang, Hainan, China Composite soil Hu et al. (2012)[117] 7. Streptomyces pluripotens MUSC 135T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Lee et al. (2014)[33] 8. Streptomyces ferrugineus HV38T Thailand Soil Ruan et al. (2015)[118] 9. Streptomyces mangrovisoli MUSC 149T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Ser et al. (2015)[119] 10. Streptomyces gilvigriseus MUSC 26T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Ser et al. (2015)[120] 11. Streptomyces mangrovi HA11110T Dongzhaigang National Nature Reserve, Hainan, China Soil Wang et al. (2015)[121] 12. Streptomyces malaysiense MUSC 136T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Ser et al. (2016)[78] 13. Streptomyces antioxidans MUSC 164T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Ser et al. (2016)[122] 14. Streptomyces humi MUSC 119T Tanjung Lumpur mangrove forest in Pahang, Peninsular Malaysia Soil Zainal et al. (2016)[123] 15. Streptomyces euryhalinus MS 3/20T Lothian Island of Sundarbans man- grove forest, India Sediment Biswas et al. (2017)[124] 16. Streptomyces colonosanans MUSC 93JT Mangrove forest in Kuching, Sar- awak, Malaysia Soil Law et al. (2017)[125] 17. Streptomyces nigra 452T Zhangzhou, Fujian Province, China Rhizosphere soil of man- grove plant Avicennia marina Chen et al. (2018)[126] 18. Streptomyces caeni HA15955T Sanya, China Mud Huang et al. (2018)[127] 19 Streptomyces monashensis MUSC 1JT Mangrove forest in Kuching, Sar- awak, Malaysia Soil Law et al. (2019)[128] Table 2. Mangrove-derived novel Streptomyces species published from year 2009 to early 2019. CONCLUSION Research on the diversity of microbial community in the class Actinobacteria originating from different environ- ments and countries has been thoroughly conducted due to their ecological importance and astonishing biotechnologi- cal potential. Nevertheless, there is still limited knowledge pertaining the diversity of Actinobacteria in the mangrove environments given that there are over 150, 000 km2 of mangroves distributed at many different parts of the world. It will be valuable to explore the diversity of Actinobac- teria from mangrove given that they have been producers of numerous useful bioactive compounds and enzymes, es- pecially from Streptomyces. The discovery novel Strep- tomyces in addition to bioprospecting of Streptomyces population from underexplored mangrove environments could therefore increase the chances of uncovering new sources of natural products for various applications. 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