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Infectious diseases are caused by pathogenic microorganisms such as bacteria, yeast, and parasitic protozoa (WHO, 2021). Their spread is increasing, producing economic crises and threatening people's safety (Gushulak and MacPherson, 2004; Vignier and Bouchaud, 2018). Over the years, microorganisms have acquired resistance to different antibiotics, antifungals, or antiparasitic; their mechanisms of resistance to different drugs have increased due to the non-specific rejection of hydrophobic chemical substances due to the impermeability of the outer membrane, the acquisition of non-specific eflux pumps, biofilms formation, and others. Thus, it is necessary to search for natural sources of antimicrobials agents that do not affect humans' and animals' health nor harm the environment (Carey and McNamara, 2015; Mir, 2022; Moglad et al., 2020; Samanta and Bandyopadhyay, 2020; Santos and Santana, 2019; Yadav et al., 2019).
Myrciaria dubia is a shrub belonging to the Myrtaceae family; native to the Amazon rainforest and grows naturally in floodable areas of streams and on the banks of rivers, lakes, or swamps of the Peruvian, Brazilian, Colombian, Ecuadorian, and Venezuelan Amazon (Castro et al., 2018; Hernández et al., 2011; Lim, 2012). The phytochemical properties of this plant have been the subject of multiple studies. They have been characterized and named as functional food, due to their high content of ascorbic acid, which varies according to the part of the fruit and its state of maturity (Alves et al., 2002; Castro et al., 2013; Cunha-Santos et al., 2019; Justi et al., 2000; Rodrigues et al., 2001; Santos et al., 2022; Villanueva-Tiburcio et al., 2010; Yuyama et al., 2002; Obregón-La Rosa et al., 2021).
M. dubia has been shown to contain carotenoids, such as β-carotene, violaxanthin, and luteoxanthin (Zanatta and Mercadante, 2007), saponins, tannins (Da Silva et al., 2022) and essential oils such as α-pinene, α-phellandrene, terpinolene, E-caryophyllene, γ-cadinene (Da Costa et al., 2022); in addition to phenolic compounds, proanthocyanidins (Fujita et al., 2013), quercetin and kaempferol derivatives (Gonçalves et al., 2010), delphinidin 3-glucoside, naringenin, cyanidin 3-glucoside, rutin, flavan-3-ol, flavonol, flavanone, and ellagic acid derivatives and catechin (Chirinos et al., 2010; Reynertson et al., 2008). Moreover, it presents phenolic compounds, such as vescalagin, castalagin (Fidelis et al., 2020); myrciarone A and B, isomyrtucommulone B, rhodomyrtone (Kaneshima et al., 2016), rosmarinic acid, trans-resveratrol, quercetin, syringic acid, methylvescalagin and cyanidin-3-glucoside, 2,4-dihydroxybenzoic acid (Do Carmo et al., 2019), myricetin and ellagic acid (De Azevêdo et al., 2014). The presence of these compounds varies according to the different parts of M. dubia (pulp, seed, peel, and leaves).
Some compounds present in M. dubia demonstrated antimicrobial activity (Figure 1) as myrciarone A from the peel (Bacillus cereus, Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis), rhodomyrtone from the peel (B. subtilis, B. cereus, M. luteus, S. aureus, S. epidermidis, Streptococcus mutans), isomyrtucommulone B from the seed (B. cereus, S. aureus, S. epidermidis, B. subtilis) myrciarone B from the seed (B. cereus, B. subtilis, S. aureus, S. mutans, S. epidermidis) (Kaneshima et al., 2017), trans-resveratrol (Schistosoma mansoni), methylvescalagin (S. mansoni, Plasmodium falciparum), quercetin, 2,4-dihydroxybenzoic acid (S. mansoni, P. falciparum from the seeds (Do Carmo et al., 2020); myricetin, syringic acid, ellagic acid, and casuarictin from the lyophilized pulp powder proved to be effective against S. aureus (Fujita et al. 2015).
Figure 1 Phenolic compounds with antimicrobial properties from M. dubia (Kaneshima et al., 2017; Do Carmo et al., 2020; Fujita et al. 2015).
Some analyzes have shown that pure phenolic compounds such as quercetin, naringenin, and kaempferol have strong antimicrobial activity (Rauha et al., 2000). Additionally, some compounds (Myricetin) present in M. dubia were found in other plant samples and demonstrated inhibitory action for Proteus vulgaris and S. aureus (Mori et al., 1987).
In this context, this review aimed to describe the antimicrobial properties of the compounds present in the pulp, seed, peel and leaves from M. dubia against bacteria, yeasts, and parasitic protozoa.
MATERIALS AND METHODS
From main databases, a search for papers published about this topic was performed (Scopus, ScienceDirect, PubMed, Wiley Online Library). Also, university repositories were consulted using the following descriptors camu camu or Myrciaria dubia and antimicrobial or bacteria or microorganisms or antimicrobial activity, preferably within the last 15 years. The information was organized according to the use of M. dubia, considering the antimicrobial properties of the compounds present in the different parts of M. dubia against different microorganisms.
RESULTS AND DISCUSSION
Inhibitory capacity of M. dubia
M. dubia contains phenolic compounds (flavonoids and phenolic acids), and they can inhibit microorganisms (Kaneshima et al., 2017; Do Carmo et al., 2020; Fidelis et al., 2020).
The antimicrobial activity of phenolic compounds is related to the kinetic curve of microbial death and minimum inhibitory concentration (MIC) (Fujita et al., 2015; Levison, 2004; Pankey and Sabath, 2004).
Antibacterial activity is due to the compounds that degrade the cell wall and/or functionally interfere with the bacterial enzymes present in these structures (Finberg et al., 2004). They cause the death of microorganisms through a process known as bactericidal action. On the other hand, bacteriostatic action occurs when the ribosomal function and protein synthesis that allows the reduction of microbial population growth are inhibited (French, 2006).
Some compounds such as myricetin have shown a bacterial inhibition of RNA synthesis (S. aureus), this inhibitory action on DNA or RNA synthesis occurs due to the B ring of flavonoids, which interacts with hydrogen bonds causing stacking of nucleic acid bases (Mori et al., 1987). Likewise, Ohemeng et al. (1993) demonstrated that flavones (ellagic acid) inhibit the catalytic activity of DNA gyrase. Similarly, some alkaloids can act as agonists or antagonists of neuroreceptors/ion channels, leading parasites (S. mansoni) to death due to neurotoxic effects (Do Carmo et al., 2020).
Kaneshima et al. (2017) and Fidelis et al. (2020) demonstrated the antimicrobial activity of M. dubia on yeasts (Candida albicans and Saccharomyces cerevisiae). There is no knowledge about the mechanism of cellular action. Nevertheless, the inhibition of protozoa is possibly due to the action of quercetin in causing mitochondrial dysfunction in these parasites (Correia et al., 2016).
M. dubia benefits. The inhibitory capacity of M. dubia constitutes an excellent alternative as a functionalized ingredient in food; it can also be used in the pharmaceutical and cosmetic industries by presenting compounds with the biological activity of interest, in which ascorbic acid and phenolic compounds stand out (Conceição et al., 2020; Inocente-Camones et al., 2014; Fidelis et al., 2020).
The phenolic compounds present in M. dubia (pulp, seed, peel and leaves) have potential alternative uses, once they show inhibitory capacity against bacteria (S. aureus, B. cereus, B. subtilis, S. mutans, S. epidermidis, E. coli, Streptococcus sanguinis) and yeasts (C. albicans, S. cerevisiae) (Camere-Colarossi et al., 2016; Conceição et al., 2020; Fidelis et al., 2020; Fujita et al. 2015; Kaneshima et al., 2017; Myoda et al., 2010; Roumy et al., 2020). Additionally, the by-products can be used after a pre-treatment of drying with hot air, spray drying, or lyophilization (De Azevêdo et al., 2014; De Azevêdo et al., 2015). Furthermore, the lyophilized pulp of M. dubia has shown greater inhibition capacity than ampicillin (Fujita et al., 2013).
Another advantage of this plant is that contributes to human health as was demonstrated in different studies (Camere-Colarossi et al., 2016; De Azevêdo et al., 2014; Moromi et al., 2016; Myoda et al., 2010). It is traditionally used in the indigenous communities of Loreto, Peru to heal various illnesses, including gingivitis, and to keep the gums of human teeth healthy (Flores, 2010; Pinedo et al., 2011).
Inhibitory capacity of M. dubia against different microorganisms
The following is a summary of studies related to the inhibition of microorganisms (bacteria, yeasts and protozoa) for compounds present in the pulp, seed, peel, and leaves from M. dubia.
M. dubia against Staphylococcus spp. The lyophilized optimized Camu-Camu seed extract (1g:20 mL of the mixture of 43.3% propanone, 40.7% water and 16% ethyl alcohol) showed inhibition against S. aureus ATCC13565 with an inhibition zone of 9.7 mm; it could block the transcription due to its castalagin and vescalagin contents (Fidelis et al., 2020). In another study, using n-hexane extract from M. dubia peel and seed; fractions of n-hexane extract (n-hexane layers and 90% acetonitrile layers) and acylphloroglucinols of n-hexane extract (1: Myrciarone A; 2: Rhodomyrtone; 3: Isomyrtucommulone B and 4: Myrciarone B) presented antimicrobial activity against S. aureus. In n-hexane extracted from the peel, MIC values were 12.50 (n-Hexane extract), 6.25 (n-hexane layers), 12.5 (90% acetonitrile layers), 1.56 (Myrciarone A) and 0.78 ug mL-1 (Rhodomyrtone). In n-hexane extracted from the seed obtained MIC value of 6.25 (n-Hexane extract, n-hexane layers, and 90% acetonitrile layers) and 1.56 ug mL-1 (Isomyrtucommulone B and Myrciarone B). Similarly, inhibitory activity was evidenced against S. epidermidis with MIC values of 6.25 (n-Hexane extract and n-hexane layers), 12.5 (90% acetonitrile layers), 3.13 (Myrciarone A) and 0.78 µg mL-1 (Rhodomyrtone) for the n-hexane extract from the peel and for the n-hexane extract from the seed were obtained MIC values of 12.5 (n-Hexane extract and n-hexane layers), 6.25 (90% acetonitrile layers and Isomyrtucommulone B) and 3.13 ug mL-1 (Myrciarone B), respectively (Kaneshima et al., 2015 and Kaneshima et al., 2017). Due to the presence of proanthocyanidins, anthocyanins, flavonoids, and phenolic acids in the lyophilized ethanol extract, M. dubia (aqueous extracts of seeds and peel) showed antimicrobial activity against S. aureus with an inhibition zone of 12 mm (De Azevêdo et al., 2014).
The methanolic extract obtained from M. dubia leaves (1.2 mg mL-1) inhibited S. epidermidis 5001 by the action of β-sitosterol and betulinic acid, which allowed the activation of drug-like chemosensory signals (Roumy et al., 2020).
Additionally, antimicrobial activity of the methanolic extract (5 mg mL-1) obtained from seed and peel of M. dubia for S. aureus was observed; the zone of inhibition for the seed extract was 2.7 mm while for the peel extract it was 3.1 mm. This is attributed to the high content of phenolic compounds (Myoda et al., 2010).
Another study showed that the antimicrobial activity of the lyophilized pulp extract of M. dubia diluted in 70% methanol inhibited S. aureus ATCC 29213 with a MIC of 0.08 mg mL-1 (0% maltodextrin or gum arabic) presenting a higher activity than ampicillin (0.26 mg mL-1), this antimicrobial activity is due to the presence of ellagic acid, tannins, cyanidin, quercetin, catechin, kaempferol, and rutin (Fujita et al., 2015).
The methanolic extracts obtained from seeds, peels, and leaves of M. dubia showed antimicrobial activity against Staphylococcus spp. as shown in Table 1. The extracts studied did not show inhibition against S. aureus. For S. epidermidis 8157, the inhibition occurred due to the action of β-sitosterol and betulinic acid present in the methanolic extract of leaves (Roumy et al., 2020).
M. dubia against Escherichia coli. The lyophilized optimized camu-camu seed extract (1:20 g:mL of the mixture of 43.3% propanone, 40.7% water, and 16% ethyl alcohol) presented antibacterial activity again E. coli IAL2064 with an inhibition zone of 6.64 mm. (Fidelis et al., 2020). This inhibition is probably caused by their phenolic compounds such as quercetin, catechin, gallic acid, ellagic acid, ellagitannins, and proanthocyanidins (Fujita et al., 2015). M. dubia fruit juice presented greater inhibitory capacity against E. coli, while for Salmonella typhi, its inhibition capacity was lower, with inhibition zones of 16.9 and 11.19 mm, respectively. This inhibition against E. coli and S. typhi is attributed to the low pH (2.09) of the fruit juice (López, 2017).
Another study carried out on lyophilized extracts obtained from 1 g of lyophilized M. dubia peel, pulp, and seeds and solvent ethanol and water (80/20, v/v) proved that the MIC for E. coli from the peel was 10 mg mL-1. Extract with the most relevant antimicrobial potential was from pulp and seed parts (Conceição et al., 2020). This action was possible due to the formation of biofilms by their flavonoids myricetin and quercetin (Arita-Morioka et al., 2018).
M. dubia against yeasts. The dry extract of M. dubia seed diluted with n-hexane (500 mg 10 mL-1) showed inhibitory activity against C. albicans (MIC ˃ 100 μg mL-1); but the resulting layer of n-hexane and 90% acetonitrile layer obtained by countercurrent partitioning (acetonitrile: water = 9:1 v/v) and two isolated compounds such as isomyrtucommulone B and myrciarone B had no effect on the yeast (Kaneshima et al., 2017). In addition, Roumy et al., 2020 showed MIC values of 0.3, 0.3 and 1.2 mg mL-1 when they used diluted methanolic extracts (12 mg mL-1) from peel, seed, and leaves respectively against C. albicans 10286. On the other hand, dry extracts from peel and seed diluted in water or DMSO to obtain concentrations of 0.1-5.0 mg mL-1 had no activity against S. cerevisiae (Myoda et al., 2010). In another study, an evaluation of the antimicrobial activity for S. cerevisiae NCYC1006 was carried out using the lyophilized optimized M. dubia seed extract (1:20 g:mL of the mixture of 43.3% propanone, 40.7% water, and 16% ethyl alcohol) presented an inhibition zone of 5.74 mm (Fidelis et al., 2020).
M. dubia against parasitic protozoa. The action of dichloromethanolic extract from M. dubia leaves against P. falciparum (clone W2), Leishmania amazonensis (IFLA/BR/67PH8), Leishmania braziliensis (IOCL 566), and Leishmania chagasi (IOCL 579) through bioassays was evaluated. This extract showed inhibitory activity against P. falciparum (chloroquine-resistant strain W2). Also, it presented greater inhibitory activity against the L. amazonensis (200 µg mL-1 of extract inhibited in 85% of the promastigote form growth) than against L. braziliensis and L. chagasi. In addition, this extract presented a growth inhibition of 50% of the parasites (IC50) equal to 2.35 μg mL-1 for P. falciparum, 190.73 μg mL-1 for L. amazonensis, and ≥ 200 µg mL-1 for L. chagasi and L. braziliensis (Correia et al., 2016).
Similarly, in an evaluation using different concentrations (10-500 µg mL-1) from lyophilized extracts of M. dubia seeds (100/200 g:mL solvent (ultrapure water: ethanol)) with parasite suspensions (0.5% parasitaemia and 2% hematocrit), obtained IC50 of 24.2 μg mL-1 for P. falciparum (juvenile stage-12h) resistant to chloroquine (W2) with 100% H2O and IC50 of 26.8 μg mL-1 for P. falciparum (trophozoite-24h) sensible to chloroquine (3D7) with 75% of H2O + 25% ethanol extract, in vitro (Do Carmo et al., 2020), this may have occurred due to the action of phenolic compounds, flavonoids (quercetin) that allows the inhibition of enzymes (β-ketoacyl-ACP-reductase, β-hydroxacylACP-dehydratase and enoyl-ACP-reductase) involved in the type II fatty acid biosynthesis pathway (Tasdemir et al., 2006).
Some microorganisms which were inhibited by the action of M. dubia can be seen in Figure 2.
Figure 2 Microorganisms that can be inhibited by M. dubia (Kaneshima et al., 2017; Do Carmo et al., 2020; Fujita et al. 2015).
M. dubia against different microorganisms.
Streptococcus mutans and S. sanguinis were inhibited using 100 μL of methanolic extracts from M. dubia pulp and seed. For both S. mutans and S. sanguinis, M. dubia seed extract had a major antibacterial (with inhibition zones of 21.36 and 19.21 mm, respectively) effect compared with the pulp extract. The MIC of methanolic seed extract against both strains could not be determined due to antibacterial activity even at very low concentrations of the extract. However, for the pulp extract, a MIC value of 62.5 μg mL-1 was observed for both strains (Camere-Colarossi et al., 2016). The use of hydroethanolic extracts of M. dubia at concentrations of 25, 50, and 75 mg mL-1 on antibacterial activity in vitro for S. mutans ATCC 35668 was evaluated, evidencing an increase in antibacterial activity directly proportional to the concentration of the extract. The concentration of 75 mg mL-1 presented an average inhibition of 18.2±0.774 mm, followed by the concentration of 50 mg mL-1 with an average inhibition of 14.6±1.055 mm and the concentration of 25 mg mL-1 with an average inhibition of 10.1±0.833 mm. The zone of inhibition of the positive control was 16.5±0.516 mm, probably rhodomyrtone is responsible for the antibacterial activity since in addition to being present in the peel and seeds it is also found in the pulp (Ruiz-Barrueto et al., 2021).
Similarly, some authors demonstrated the inhibition of Erwinia carotovora subsp. carotovora by M. dubia, the following peel extracts revealed that 50% acetonic extract presented high inhibition, followed by ethanolic extract (50%), and chloroform extract (50%). For Pseudomonas cichorium, ethanolic extract (50%) presented greater inhibitory capacity followed by acetonic and chloroformic extracts (Flores and Naupari, 2017).
The methanolic extract of M. dubia seed showed activity against P. aureginosa ATCC25783 with MIC values of 1.2 mg mL-1 while P. aureginosa 8131 had no activity. On the other hand, the methanolic extracts of peel, seed and leave of M. dubia showed activity against Enterococcus faecalis T25-17 with MIC values of 0.3 mg mL-1 (peel and leave), 1.2 mg mL-1 (seed); in the same way, for Enterococcus spp. 8153 with MIC values of 0.3 mg mL-1 (peel and seed) (Roumy et al., 2020).
In another study, Nile tilapia (Oreochromis niloticus) tests were carried out on fish supplemented with 500 mg of M. dubia per kilogram of feed, it was observed a greater immune response of the fish against Aeromonas hydrophila in their swim bladder. The high ascorbic acid content of this plant increases the activity of leukocytes against pathogens and makes neutrophils in the blood increase and migrate to the site of infection to recognize and destroy pathogens, as well as the number of lymphocytes that generate antibodies. Furthermore, lysozyme serum exhibits the ability to hydrolyze peptidoglycans from the cell wall of pathogens (Yunis-Aguinaga et al., 2016).
Additionally, the B rings of the flavonoids interact with the hydrogens of the nucleic acids, inhibiting their synthesis; others can act at the cellular level of the bacteria, causing the release of components that can inactivate the bacteria (Cushnie and Lamb, 2005).
In another study, the optimized lyophilized M. dubia seed extract (1:20 g:mL of the mixture of 43.3% propanone, 40.7% water, and 16% ethyl alcohol) inhibited P. aeruginosa IAL1853 (8.72 mm), S. enteritidis S 2887 (6.82 mm), S. typhimurium IAL2431 (6.42 mm), B. cereus ATCC14579 (9.04 mm), Listeria monocytogenes ATCC7644 (8.58 mm) (Fidelis et al., 2020). However, Da Silva et al. (2021) studied the level at which M. dubia powder 0.0, 2.0, 3.5, or 5.0% (w/w), mixed with 200 g of ground meat and Salmonella enterica ser. typhimurium (5 log CFU g-1). The concentration of CPP at 5% had an inhibition value of 5.089 log UFC g-1 S. enterica compared to control without CPP (5.121 log UFC g-1 S. enterica), indicating the rapid decrease in the concentration of Salmonella when increasing the concentration of CPP by interfering with the adaptability of the pathogens; however, it does not extend the shelf life of ground meat.
Furthermore, Willemann et al. (2020) showed that 2 mgof lyophilized aqueous extract of camu camu seed exocarp inhibited the growth of L. monocytogenes (11.9 mm), P. aeruginosa (8.9 mm), S. typhimurium (8.9 mm), S. enteritidis (10.5 mm) and B. cereus (8.8 mm).
CONCLUSIONS
Phenolic compounds of M. dubia (peel, pulp, seeds, and leaves) such as polyphenols, flavonoids, and anthocyanins have been studied and categorized as responsible for the inhibition of different Gram-positive bacteria (L. monocytogenes, S. aureus), Gram-negative bacteria (E. coli, S. typhimurium, S. enteritidis, P. aeruginosa, S. tiphy), yeasts (S. cerevisiae, C. albicans), protozoa (P. falciparum, L. amazonensis, L. braziliensis, L. chagasi) and other pathogenic microorganisms that could affect food, whose action could be due to functional interference of bacterial enzymes in their structures, bacteriostatic action on ribosomal function or protein synthesis and blocking of RNA or DNA synthesis by catalytic inhibition of DNA gyrase. The inhibition of protozoa is possibly due to the action of quercetin in causing mitochondrial dysfunction in these parasites.
The inhibitory capacity of M. dubia extracts might not affect beneficial probiotic bacteria and could be applied in foods after further studies on the subject.
Further fractionation and purification studies of compounds present in the different parts of M. dubia and evaluated against pathogenic and food spoilage microorganisms are required. It is also necessary to explain the mechanism of action of inhibition of the different compounds at the cellular level.
CONTRIBUTION OF THE REVIEW
Information regarding the antimicrobial capacity of M. dubia, an Amazonian fruit from countries such as Peru, Brazil, Colombia, and Venezuela, has been identified and organized, offering a possible alternative to be used as an antimicrobial additive in the food industry after further studies.
