Antimicrobial Secondary Metabolites from the Mangrove Plants of Asia and the Pacific

Microbes such as the White Spot Syndrome Virus account for severe losses in the shrimp farming industry globally. This review examines the literature on the mangrove plants of Asia and the Pacific with antibacterial, antifungal, or antiviral activities. All of the available data published on this subject were collected from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1968 to 2022. Out of about 286 plant species, 119 exhibited antimicrobial effects, and a total of 114 antimicrobial natural products have been identified including 12 with MIC values below 1 µg/mL. Most of these plants are medicinal. The mangrove plants of Asia and the Pacific yield secondary metabolites with the potential to mitigate infectious diseases in shrimp aquaculture.


Introduction
The global shrimp and prawn aquaculture industry is regularly threatened by outbreaks of microbial infections [1] that require antibiotics, antifungals, and antiviral agents participating in the selection of multidrug-resistant strains of microbes, pausing the grim scenario of the emergence of a "superbug" that could wipe out the global supply of penaeids [2]. In this context, there is an urgent necessity to search for antimicrobial agents with original chemical frameworks, and such molecules could come from the flora of Asia and the Pacific, which is the oldest, largest, and richest on Earth, especially seashores, tidal rivers, and mangrove plants.
Mangroves are ecosystems of the tropical and subtropical seashores, estuaries, and tidal rivers characterized by a halophytic flora of mainly trees and shrubs divided into true mangrove or mangrove-associated species. True mangrove species are restricted to mangroves whereas mangrove-associated species are found along the seashores, and even inland. There are estimates of about 54 true mangrove plant species and 60 mangroveassociated species globally, which are home to shrimps, prawns, crabs, and fish [3]. Most mangrove species grow in Asia and the Pacific [4]. Examples of true mangrove plant species are Excoecaria agallocha L. (land zone), Bruguiera gymnorhiza (L.) Savigny, Rhizophora stylosa Griff. (intermediate zone), Avicennia alba Bl, and Aegiceras corniculatum (L.) Blanco Table 1. Ferns and cycads from the mangroves, tidal rivers, and the seashores of Asia and the Pacific with antibacterial and/or antifungal activity. Bold: true mangrove plants [3]. +: Activity of extract(s) reported in the literature.

Subclass Cycadaceae
The ethyl acetate extract of Cycas rumphii Miq. developed halos against Staphylococcus albus whereas the methanol extract (20 mg/mL solution per disc) hampered the growth of S. aureus and E. coli [22]. Later, the methanol extract of leaves (paper disc impregnated with 20 mg/mL solution) repressed S. aureus (ATCC 25953) [22]. Note that the Cycadaceae have not been much studied for their antimicrobial effects (Table 1) [23].

Subclass Magnoliidae
Mangrove plants in this subclass produce most of, and a broad spectrum of antimicrobial secondary metabolites.

Clade Protomagnoliids
Plants in the clade are not found in mangroves.

Clade Core Eudicots
Plants in this clade are not found in mangroves.

Clade Core Eudicots
Plants in this clade are not found in mangroves.
Antimicrobials in the family Sapindaceae are mainly triterpene saponins and triterpenes the later soluble lipid. The petroleum ether of Allophylus cobbe (L.) Raeusch strongly inhibited the growth of Shigella sonnei, Salmonella paratyphi, and C. neoformans with the MIC values of 31.2 µg/mL [178][179][180][181]. The methanol extract of the leaves of Harpullia arborea (Blanco) Radlk repressed a broad-spectrum of bacteria and fungi [182] whereas the ethanol extract of leaves was active against HCV [183] on probable account of simple phenolic glycosides [184].
Order Caryophyllales: In the order Caryophyllales, a fatty acid fraction of Sesuvium portulacastrum (L.) L. (Aizoaceae) as well as the essential oil moderately hindered a broadspectrum of bacteria and fungi [194,195]. The ethanol extract of leaves was active against HBV [130]. The polar organic extract of Salicornia brachiata Miq. and Suaeda maritima (L.) Dumort. (Chenopodiaceae) displayed broad-spectrum antibacterial, antifungal, and antiviral properties [196,197]. The fatty acid fraction of the aerial parts of S. brachiata Miq. moderately restrained B. subtilis S. aureus and methicillin-resistant S. aureus [198]. The ethanol extract of the leaves of S. maritima was active against the EMCV [130]. The organic polar extract of the true mangrove tree Aegialitis rotundifolia Roxb. and Limonium tetragonium Bullock (Plumbaginaceae) are antibacterial and antifungal [199,200]. The methanol extract of the roots of L. tetragonium Bullock blocked HIV-1 reverse transcriptase [201].
The ethanol extract of the bark (500 µg/disc) of the true mangrove tree Aegiceras corniculatum (L.) Blanco (Aegicerataceae) developed a halo with a broad spectrum of bacteria [28], while the hexane extract of leaves inhibited the growth of Mycobacterium tuberculosis (H 37 R v ) with the MIC value of 50 µg/mL [212]. The oleanane triterpene acornine 2 (65) isolated from the bark hindered yeasts and filamentous fungi (Table S2) [212]. The ethanol extract of fruits inhibited NDV and SFV [130].

Antimicrobial Extracts and Compounds from Mangrove and Mangrove-Associated Plants with the Potential to Be Used for Shrimp Farming
According to Kuete (2010), crude extracts with MIC values less than 100 µg/mL are antimicrobial [10]. Here, we define a very strongly active extract with a MIC value below 10 µg/mL. An isolated compound is defined as very strongly active for a MIC value below or equal to 1 µg/mL (as well as less than 1 µg/thin layer chromatography), strongly antibacterial (or antifungal) for a MIC value above 1 µg/mL and equal to or below 50 µg/mL, moderately antibacterial (or antifungal) for a MIC from 50 and below 100 µg/mL, weakly antibacterial (or antifungal) for a MIC from 100 and below 500 µg/mL, very weakly antibacterial (or antifungal) for a MIC ranging from 500 to below 2500 µg/mL, and inactive for a MIC value above 2500 µg/mL.
For antiviral principles, we suggest that a compound with an IC 50 value below or equal to 1 µg/mL is very strongly active, for an IC 50 value above 1 and equal to or below 20 µg/mL strongly antiviral, for an IC 50 above 20 and below or equal to 100 µg/mL moderately antiviral, for an IC 50 above 100 and below or equal to 500 µg/mL weakly antiviral, for an IC 50 ranging from above 500 to below or equal to 2500 µg/mL very weakly antiviral, and inactive with an IC 50 value above 2500 µg/mL.
(iv) We note that most of these principles are hydrophilic or amp

Spectrum of Activity of Antimicrobial Extracts and Principles from Mangrove and Mangrove-Associated Plants
The following observations can be made: (i) No reports on the only lycopod associated with mangrove are available.
(ii) Of the 26 ferns, nine had antibacterial effects and six are antifungal, and no antiviral activities were reported. The only antimicrobial principle from ferns thus far is the strong antibacterial (Gram-positive) stenopalustroside A [13] (Table 1). (iii) The cycad associated with mangroves has antibacterial effects. (iv) No reports on the only pine tree associated with mangrove are available.
(v) Of the 51 monocots, 11 displayed antimicrobial effects, of which eight had antibacterial activity, six with antiviral activity, and none reported with antiviral properties. Active principles isolated were phenolics such as the flavanol naringenin (9) in the Pandanaceae, antibacterial, antifungal, and antiviral orchidaceous phenanthrenes as well as the flavones and antifungal hydroxycinnamic acid of Poaceae (Table 2) (vi) Of the 207 dicots, 92 had antimicrobial effects including 78 antibacterial, 39 antifungal, and 25 antiviral effects. A total of about 80 antimicrobial principles were isolated (Table S2). (vii) Aqueous and organic polar extracts of plants from the mangrove presented activity against Gram-positive and Gram-negative bacteria, filamentous fungi and yeasts, enveloped and non-enveloped viruses, DNA, and RNA viruses (Table S2). (viii) The extract of P. pinnata [262] and gallic acid (21) abounds notably in the true mangrove trees Rhizophora apiculata Bl. and Aegiceras corniculatum (L.) Blanco is a protected shrimp against WSSV [84] as well as an aqueous extract of the true mangrove tree C. tagal (Perr.) C.B. Rob. [263]

Medicinal Use of Mangrove and Mangrove-Associated Plants
One could suggest the use of medicinal plants as a more sustainable alternative to chemotherapy in paenid aquaculture. Therefore, the possible beneficial effect of mangrove and mangrove-associated plants for the sanitation of shrimp farms is reinforced by the observation that 85 plants were used for the treatment of infectious diseases including mainly diarrhea, dysentery, and wounds   (Table S1). The pharmacological effect of these plants involves active principles that are potentially able to act on paenids, which could be examined further.

Mangrove and Mangrove-Associate Plants as Remediation of Shrimp Farming?
Shrimp and prawn farms are regularly affected by (+)-RNA viruses such as the Taura syndrome virus, Yellow head virus, and Gill-associated virus as well as DNA viruses (WSSV, Monodon Baculovirus) and Gram-negative bacteria such as Hepatobacterium penaei and Vibrio spp. [295]. Synthetic drugs are being used in an attempt to evade economic losses but threaten the environment and contribute to the selection of multidrug-resistant pathogenic microorganisms. Being able to produce antimicrobial principles (some of them water soluble like ellagic acid), mangrove and mangrove-associated plants could be used as a source of natural agents and/or afford ecological systems to combat the infections with shrimps and prawns. Polar organic and aqueous extracts of most mangrove and mangrove-associated plants exhibit broad-spectrum antibacterial, antifungal, or antiviral properties in vitro, suggesting that antimicrobial secondary metabolites from plants and plant litter in the sea and brackish waters could afford some control against the overgrowth of pathogenic microbes. Of note, P. pinnata ethanol extract of leaves given to Penaeus monodon as part of feed at the dose of 300 µg/g of body weight/day evoked some levels of protection against WSSV [262]. Gallic acid (21), which abounds notably in the true mangrove trees R. apiculata and A. corniculatum is strongly antiviral and protected shrimps against WSSV [84]. Gallic acid (21) may, at least in part, account for the fact the aqueous extract of the true mangrove tree C. tagal given at the dose of 10% of the body weight, twice a day, protected shrimps against WSSV [263]. Furthermore, gallic acid (21) decreases microbial proliferation in mangrove soil [296] as well as the growth of microalgae [297], which contribute to a decreased production in shrimp aquaculture [298], at least in part, to the alteration in the shrimp's immune system [299]. The control of pathogenic bacteria may have some beneficial effects for the symbiotic bacteria of shrimp against pathogenic microorganisms [300]. Furthermore, phenolic acids from mangrove and mangrove-associated plants could, by chelation, protect shrimps against toxic metals including cadmium [301,302]. Therefore, it is possible to extend the protective effect of mangrove and mangrove-associated plants to fisheries and crab farming, the latter being affected by Vibrio species [165]. Another interesting feature of mangrove plants is that they are a host for microorganisms for Actinomyces producing antibacterial principles [303].

Conclusions
Plants from the Mangroves of Asia and the Pacific produce a vast array of antimicrobial secondary metabolites that could be further examined for their possible development into medications to control microbial outbreaks in aquaculture. In parallel, growing plant mangroves in aquacultures and promoting mangrove-associated aquaculture could be beneficial. The rise in the global population and the imperative to supply shrimps, prawns, crabs, and fish globally requires the preservation of mangroves.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/md20100643/s1, Figure S1: Natural products from the plants of the mangroves, tidal rivers, and the seashores of Asia and the Pacific; Table S1: Plants from the mangroves, tidal rivers, and the seashores of Asia and the Pacific, Table S2: Antimicrobial activity of extracts and isolates from the Dicotyledons from the mangroves, tidal rivers, and the seashores of Asia and the Pacific.