Myrtaceae family: an update on plant-derived bioactive compounds against bacteria that affect the respiratory system

Abstract

Respiratory bacterial infections are a cause of morbidity and mortality worldwide; most of these infections respond well to antibiotic therapies, although several factors cause bacteria to become increasingly resistant, leading to a concerning public health problem. Hence, researchers have sought new antibiotics that can replace or enhance the effectiveness of existing drugs. Given this scenario, this review is based on original articles from the PubMed and Science Direct databases published from May 2015 to February 2022 that reported the potential of essential oils, extracts, and formulations containing Myrtaceae and nanoparticles against bacteria that affect the respiratory system.

Key words
antibacterial; Myrtaceae; phytochemistry; respiratory infection; therapy

Resumo

As infecções bacterianas do sistema respiratório são causa de morbidade e mortalidade em todo o mundo. A maioria dessas infecções responde bem às terapias antibióticas, porém, diversos fatores fazem com que as bactérias se tornem cada vez mais resistentes, causando um grave problema de saúde pública no mundo. Devido a este problema, têm-se procurado novos antibióticos que possam substituir ou aumentar a eficácia dos fármacos existentes. Esta revisão é baseada em artigos originais obtidos através de buscas nas bases de dados PubMed e Science Direct publicados no período de maio de 2015 a fevereiro de 2022, que relataram o potencial de óleos essenciais, extratos e formulações contendo Myrtaceae e nanopartículas contra bactérias que afetam o sistema respiratório.

Palavras-chave
antibacteriano; Myrtaceae; fitoquímica; infecção respiratória; terapia

Introduction

Respiratory infections are among the most common diseases, causing morbidity and mortality worldwide. Most of these infections respond well to antibiotic therapies, although several factors cause the pathogens to develop resistance, including the indiscriminate use of this type of medication, cross-resistance, and lack of new drugs, among others (Torres et al. 2021; Troeger et al. 2018).

The emergence of multidrug-resistant (MDR) bacteria increases morbidity and mortality rates, hospital stay lengths, and patient treatment costs, making bacterial antibiotic resistance a major public health problem (Woolhouse et al. 2016). In 2017, the World Health Organization published a list of antibiotic-resistant “priority pathogens” containing a variety of microorganisms, including bacteria involved in respiratory infections, that pose the greatest threat to human health (WHO 2017). Each year, 700,000 people worldwide die of MDR infections, and if no action is taken, over 10 million deaths are estimated to occur by 2050 (Tillotson & Zinner 2017). Therefore, searching for new antibiotics capable of overcoming microbial resistance is critical.

Given these circumstances, bioprospection research has sought to identify plants from which new drugs may be produced using essential oils, crude plant extracts, isolating active components, combinations of antibiotics, nanotechnology, and other approaches. In the research and development sector of the pharmaceutical industry, phytochemicals are a source of new molecules leading to new drug development, and it is estimated that 30-50% of modern drugs are based on natural products, especially plants (Boucher et al. 2017; Newman & Cragg 2020).

Various plant species from the Myrtaceae family are used for medicinal purposes, including the treatment of infectious diseases, and the underlying mechanism of action is thought to be related to the plants’ astringent properties. Given this context, this study will review the essential oils, extracts, and nanoproducts synthesized from plants of the Myrtaceae family and employed against respiratory infection-causing bacteria.

Material & Methods

A search was performed in the PubMed and Science Direct databases for original scientific articles published from May 2015 to February 2022, and ‘Myrtaceae used as a clinical antibacterial’ was used as the search term. The articles included in this review were selected based on studies with plants of the Myrtaceae family that evaluated the in vitro antibacterial activity against bacteria involved in respiratory infections.

Results & Discussion

Myrtaceae family

Myrtaceae is a family of plants present in the main group of angiosperms, comprising 145 genera and 5,970 species (The Plant List 2013). The species that make up this family are predominantly distributed in the Southern Hemisphere and mostly found in the Neotropical and Australian regions (Fig. 1) (Sytsma et al. 2004; Heywood et al. 2007). In Brazil, there are 140 genera within the Myrtaceae family and 6,000 species (Proença et al. 2022). Due to its chemical composition, this family has numerous bioactive properties, comprising phenolic and polyphenol compounds such as flavonoids, phenolic acids, tannins, stilbenes, lignans, coumarins, tocopherols, functional lipids, and carotenoids (Fig. 2) (Duarte & Paull 2015).

Figure 1
Geographic distribution of plants in the Myrtaceae family.

Figure 2
a-e. Molecular representation of the main compounds present in the chemical composition of plants in the Myrtaceae family - a. Flavonoid; b. Stilbene; c. Coumarin; d. Phenolic acid; e. Carotenoid.

The Myrtaceae family consists of various species, including Eucalyptus globulus Labill. (eucalyptus), Eugenia uniflora L. (pitanga), Campomanesia adamantium (Cambess.) O. Berg (guabiroba), Melaleuca alternifolia (Maiden & Betche) Cheel (tea tree), Psidium guajava L. (guava), Psidium cattleianum Sabine (araçá), Syzygium cumini (L.) Skeels (jambolan), and Syzygium aromaticum (L.) Merr. & L. M. Perry (clove) (The Plant List 2013).

1. Bioactive species of Myrtaceae

and their identified compounds in treating respiratory infection-causing bacteria

1.1 Essential oils

Essential oils (EO) are natural volatile compounds present in plants, with over 3,000 secondary metabolites. Among these metabolites, about 500 are volatile compounds, including monoand sesquiterpenes, terpenoids, aldehydes, and phenols (Schelz et al. 2006). Some of these constituents have proven biological properties, such as anti-inflammatory and antibacterial effects (Lazarini et al. 2018; Schelz et al. 2006). The chemical constituents and activity of EOs of different species of the Myrtaceae family against respiratory infection-causing bacteria are described throughout the text and in Table S1 (available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;).

1.1.1 Genus Eucalyptus

The genus Eucalyptus, popularly known as eucalyptus, represents over 700 species worldwide. Luís et al. (2016) investigated Eucalyptus globulus EO and, through gas chromatography coupled with mass spectrophotometry (GC-MS), found 45 constituents in their chemical composition, the main ones being 1.8-cineol (eucalyptol) (63.81%), α-pinene (16.06%), and aromadendrene (3.68%). Salem et al. (2018) found 67 volatile constituents in E. globulus EO and differences depending on the plant stage; eucalyptol (13.23%) was observed in the vegetative stage, while p-cymene was found as the major compound in the full flowering (32.19%) and fruiting stages (37.82%) (Tab. S1, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;). The authors also tested the antibacterial activity of E. globulus and E. radiata Hook. EOs against several microorganisms, and the E. globulus EO showed promising activity against Acinetobacter baumannii ATCC 17978 with a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 4 µL mL^-1, while E. radiata EO presented a MIC and MBC of 8 µL mL^-1 against this bacterium.

The researchers evaluated the combination of E. globulus EO with conventional antibiotics (cefoperazone, piperacillin, ciprofloxacin, tetracycline, chloramphenicol, and gentamicin) and found that this was effective against A. baumannii. In fact, the authors noted that the best fractional inhibitory concentration indices (FICI) were achieved by combining chloramphenicol with E. globulus EO, leading to modal values of 0.12 (A. baumannii ATCC 17978) and 0.09 (A. baumannii ATCC 19606), followed by combining the same antibiotic with E. radiata EO, leading to modal values of 0.12 against A. baumannii ATCC 17978 and 0.06 against A. baumannii ATCC 19606. Salem et al. (2018) identified a MIC of 4 mg mL^-1 in the E. globulus EO against Staphylococcus aureus ATCC 6816 in all the tested stages of the plant; for methicillin-resistant S. aureus (MRSA), the researchers found an even lower MIC of 2 mg mL^-1 in the vegetative stage and 4 mg mL^-1 in the other stages. For Klebsiella pneumoniae CIP 104727, the MIC was 4 mg mL^-1 in all EOs of the different parts of the plant tested. The antibacterial activity of this EO can occur due to its chemical composition since 1.8-cineol and p-cymene can act synergetically, potentiating the effects (Veras et al. 2012). In the checkerboard test, when testing E. globulus EO with ampicillin, the authors found partial synergism with a FICI of 0.53 μg mL^-1 compared to MRSA and FICI of 1μg mL^-1 compared to K. pneumoniae CIP 104.727, showing additivity (Salem et al. 2018).

Seventy-two compounds were found in E. radiata EO, of which most were limonene (68.51%), α-terpineol (8.60%), and α-terpinyl acetate (6.07%) (Luís et al. 2016). The authors tested the antibacterial potential of E. globulus and E. radiata EOs against standard strains: Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 13883, A. baumannii ATCC 17978, and A. baumannii ATCC 19606 and three more clinical isolates: P. aeruginosa PA 08, P. aeruginosa PA 12/08, and K. pneumoniae KP 08, and the MIC test revealed that the E. radiata EO had better antibacterial activity, proving to be bactericidal, as the MIC were lower than the E. globulus EO against P. aeruginosa PA 08 and K. pneumoniae KP 08. Furthermore, Luís et al. (2016) tested the combination of conventional antibiotics (cefoperazone, piperacillin, ciprofloxacin, tetracycline, chloramphenicol, and gentamicin) with E. radiata EO and found modal values of 0.12 and 0.06 against A. baumannii ATCC 17978 and A. baumannii ATCC 19606, respectively.

E. camaldulensis is also a species within the genus Eucalyptus with biological properties, in addition to being tested against MDR strains such as A. baumannii (Jazani et al. 2012). Knezevic et al. (2016) evaluated two types of E. camaldulensis EOs collected from two coastal areas of Montenegro (Europe - Herceg Novi (EuHN) and Bar (EuB)). Fourty-three compounds were identified in these EO, and the most representative were spatulenol (EuHN - 18.90%; EuB: 21.39%), krypton (EuHN - 7.59%; EuB - 12.15%), p-cymene (EuHN - 5.35%; EuB - 7.56%), and 1.8-cineole (EuHN - 7.62%; EuB - 1.95%). The antibacterial activity was assessed against three standard strains: A. baumannii ATCC 19606, A. baumannii ATCC BAA747, and A. baumannii NCTC 13420, and twenty more A. baumannii MRD isolated from clinical and outpatient wounds. The authors found that MIC for the reference bacteria ranged from 1 to 2 μL mL^-1 and from 0.5 to 2 μL mL^-1 for the isolates in both tested EOs. In addition, the researchers observed a synergistic interaction when combining the E. camaldulensis EO with ciprofloxacin, producing FICI values below 0.5 μL mL^-1 against two A. baumannii isolates (Aba-4914 and Aba-5055) and an additive effect against Aba-6673. Moreover, a synergistic interaction occurred when the EO was tested with gentamicin against Aba-4914, decreasing the concentrations of the antibiotic, as was shown by combining the EO and polymyxin B, which showed synergistic potential against three multi-resistant microorganisms (Knezevic et al. 2016).

1.1.2 Genus Melaleuca

The species of Melaleuca alternifolia is used as a topical antiseptic and anti-inflammatory agent (Saller et al. 1998). The EO extracted from this plant has antibacterial activity against Gram-positive and Gram-negative bacteria (Carson et al. 1995, 2000). Oliva et al. (2018) employed the GC-MS technique and identified three main constituents in M. alternifolia EO, namely: terpinene 4-ol (35.4%), eucalyptol (15.2), and α-pinene (12.4%). Imane et al. (2020) utilized the same approach and found terpinene 4-ol (13.5%) and α-pinene (13.1%), although in smaller quantities, with α-carene (17.4%) being the major compound. When determining the antimicrobial activity, the following microorganisms were used: methicillin-sensitive S. aureus (MSSA) ATCC 29213, MRSA - clinical isolate (skin), extended-spectrum beta-lactamases producer carbapenem-sensitive Klebsiella pneumoniae (ESBL-CS-Kp) - clinical isolate (urine), carbapenem-resistant K. pneumoniae (ESBL-CR-Kp) - clinical isolate (urine), carbapenem-resistant A. baumannii (CR-Ab) - clinical isolate (sputum), and carbapenem-resistant P. aeruginosa (CR-Pa) - clinical isolate (bronchoalveolar lavage). The results showed that M. alternifolia EO was active, with MIC and MBC of 0.25 µg mL^-1 for CR-Ab and ESBL-CR-Kp, 0.50 µg mL^-1 for ESBL-CS-Kp, and MIC of 0.50 µg mL^-1 and MBC of 2.0 µg mL^-1 for MRSA. The EO was active against MSSA ATCC 29213, with MIC and MBC of 1.0 and 2.0 µg mL^-1, respectively, and CR-Pa MIC of 1.0 µg mL^-1 and MBC of 1.0 µg mL^-1; however, it was possible to note that the EO was bactericidal against all the tested bacteria (Oliva et al. 2018).

Imane et al. (2020) also observed antibacterial activity against the microorganisms evaluated, with a MIC of 4.42 mg mL^-1 against MRSA NCTC 12493 and 2.21 mg mL^-1 against a S. aureus isolate, both being bactericidal. When evaluating the same EO against K. pneumoniae ATCC 700603, the authors obtained a MIC of 8.84 mg mL^-1. These findings highlight how M. alternifolia EO is a promising alternative in treating infections caused by MDR Gram-negative microorganisms, considering that various infections, such as hospital pneumonia, are caused by these bacteria (especially A. baumannii and K. pneumoniae). In addition, this EO is a promising inhalable alternative for local therapy in the case of respiratory infections (Ekren et al. 2018; Li et al. 2016; Oliva et al. 2018).

In the checkerboard assay, Oliva et al. (2018) tested some antibiotics, including amikacin, oxacillin, cefazolin, vancomycin, and rifampicin for MSSA (ATCC 29213) and MRSA; for the other bacteria, the combination of EO with amikacin, meropenem, and colistin was evaluated. The results showed a synergistic effect in subinhibitory concentrations of the combinations of M. alternifolia EO and amikacin, oxacillin, and cefazolin against both Gram-positive bacteria and when tested with amikacin, meropenem, and colistin against all Gram-negative microorganisms.

The chemical characterization of the M. leucadendra EO was analyzed by GC-MS, revealing 45 compounds, which accounted for 99.73% of the total oil composition. Monoterpenoids dominated the EO (77.43%), with four primary compounds: α-pinene (9.06%), limonene (32.00%), 1,8-cineole (17.32%), and viridiflorol (14.89%) (Bautista-Silva et al. 2020).

Bautista-Silva et al. (2020) achieved a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria using M. leucadendra EO. Among the microorganisms tested, K. pneumoniae ATCC 13883 had one of the highest MIC (62.5 mg mL^-1), while the EO showed the lowest antibacterial activity (31.2 mg mL^-1) against P. aeruginosa ATCC 27853 and S. aureus ATCC25923. The authors evaluated the activity of the M. leucadendra EO against the tested strains (exponential stage) during the different periods, in which it was possible to observe a reduction in cell viability, decreasing bacterial growth for K. pneumoniae at concentrations below the MIC (62.5 mg mL^-1).

1.1.3 Genus Syzygium

Imane et al. (2020) also evaluated the EO of cloves, as it is popularly known, despite receiving the scientific name of Syzygium aromaticum L. Merr. & L. M. Perry (The Plant List 2013). In the chemical characterization of the S. aromaticum EO, the authors found 3-allyl guaiacol (42.6%), eugenol acetate (15.9%), and caryophyllene (15.5%) as the three main compounds. This EO showed antibacterial activity against MRSA NCTC 12493, K. pneumoniae ATCC 700603, and a S. aureus isolate with MIC and MBC of 0.21 mg mL^-1 (Tab. S1, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;) (Imane et al. 2020).

1.1.4 Genus Pimenta

The genus Pimenta has various medicinal purposes; Pimenta dioica (L.) Merr. and Pimenta racemosa (Mill.) J.W. Moore are the most recognized species within this genus as they have pharmacological effects due to their rich EO composition (Chaverri & Cicció 2015; Ismail et al. 2020). Ismail et al. (2020) tested EO extracted from P. dioica and P. racemosa leaves and berries and found β-myrcene as the main constituent in the chemical composition of P. dioica leaves (44.1%), 1.8-cineol (18.8%), and limonene (11.7%). The EO extracted from the berry had similar major compounds: β-myrcene (13.9%), limonene (4.6%), and β-linalool (3.6%), although β-myrcene and limonene were found in smaller quantities. These authors tested the four EO against the standard strain of A. baumannii ATCC 19606 and fourteen MDR clinical isolates of A. baumannii and observed that the P. dioica EO extracted from leaves and berry presented MIC ranging from 0.51 to 5.2 µg mL^-1 against the fifteen microorganisms evaluated. Thus, the EO of this plant showed a more substantial antimicrobial potential in terms of lower MIC than the other EO tested.

The P. racemosa EO was also analyzed by Ismail et al. (2020); they identified three main compounds: β-myrcene, limonene, and β-cis-ocimene in the EO extracted from leaves and berries, although in different amounts (39.6, 15.5, and 2.8% for the former and 42.3, 14.3, and 4.6% for the latter). All EOs tested showed a bactericidal effect after 24 h incubation; both EO prepared with P. racemosa leaves and berries exhibited the same bactericidal activity at 2.08 and 2.76 µg mL^-1, respectively, although the P. racemosa EO had less pronounced action than the P. dioica EO (Ismail et al. 2020).

1.1.5 Genus Rhodamnia

Rhodamnia dumetorum (DC.) Merr. & L.M. Perry is a plant species originally from Cambodia. In the study by Houdkova et al. (2018), the chemical characterization of EO extracted from R. dumetorum leaves was evaluated by GC-MS equipped with two capillary columns of different polarities (HP-5MS and DB-17MS). In addition, a flame ionization detector coupled to a quadrupole selective mass detector, in which 72 constituents were identified, was equivalent to 91.37% (HP-5MS) and 90.48% (DB-17MS) of the total content. The major volatile compounds were caryophyllene epoxide (33.29/4.51%), α-pinene (26.09/73.53%), and humulene-1,2-epoxide (2.48/0.39%) (Tab. S1, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;). Antibacterial activity was performed against bacteria related to respiratory tract infections (Haemophilus influenzae ATCC 49247, S. aureus ATCC 29213, and Streptococcus pneumoniae ATCC 49619). Concentration values of ˃1024 μg mL^-1 were found against all tested microorganisms. The R. dumetorum EO showed moderate cytotoxicity (IC₅₀ 1.98 ± 1.17 μg mL^-1) against pulmonary fibroblast cells (MRC-5) (Houdkova et al. 2018).

1.1.6 Genus Eugenia

Pereira et al. (2017a) evaluated Eugenia jambolana Lam. EO (EjEO) and found 26 compounds in its composition (98.93%), with α-pinene (48.09%) and nerolidol (8.73%) as the major constituents. The authors analyzed the antibacterial activity of EjEO against S. aureus ATCC 25923, P. aeruginosa ATCC25853, and isolates of S. aureus SA 358 and P. aeruginosa PA 03, observing that the EO had a better effect against the strain of S. aureus (128 µg mL^-1) according to the in vivo assays. In the technique of modulating antibiotic activity by direct contact, the combination of EjEO with amikacin or gentamicin increased the MIC against S. aureus, obtaining an antagonistic effect; in the gaseous contact method with the same EO and amikacin or erythromycin against P. aeruginosa, the halos decreased, thus having a synergistic activity (Pereira et al. 2017a). When assessing EO with ciprofloxacin and norfloxacin using the same technique, however, with exposure to red and blue light-emitting diodes (LED), the halo increased, indicating synergism. Phototherapy combined with EO may be an option to reduce the excessive use of antimicrobials, as the application of LED lights positively affected Gram-positive and Gram-negative microorganisms (Pereira et al. 2017a; Wagner 2011).

Eugenia uniflora L. is a native species of Brazil and popularly known as “pitangueira,” “pitanga,” and “pitanga-vermelha,” occuring throughout Brazil (Fouqué 1981; Villachica 1996; Mazine et al. 2022). Pereira et al. (2017b) chemically characterized E. uniflora EO (EuEO) and found isofuran-germacrene (65.80%) as the main compound, followed by germacra-3,7,9-trien-6-one (16.19%) and β-element (4.47%). In the antibacterial assay using the broth microdilution technique for S. aureus ATCC 25923, the researchers obtained a MIC of 256 µg mL^-1; however, in the test of bacterial resistance modulation by direct contact against the same microorganism, when the EuEO was combined with commercial antimicrobials (amicanine and gentamicin), there was a reduction in the concentration of the antibiotic, resulting in synergism. This is the opposite of what occurred for P. aeruginosa, which presented antagonism when combining EuEO with amikacin and erythromycin (Pereira et al. 2017b). The antagonism resulting from the combination of EuEO with aminoglycosides against P. aeruginosa may occur due to a complex barrier system formed by the membrane (phospholipids, lipopolysaccharides, and proteins) that allows a high degree of impermeability to antimicrobials (Lambert et al. 2001).

Essential oils are a viable alternative to antibiotics in the fight against microorganisms (Tab. S1, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;). The antimicrobial activity of these EO seems more potent than the sum of their separate components, demonstrating the synergy between the numerous constituents present in their chemical composition. Therefore, using EO extracted from plants is an important research theme given the need to find substances that are not resistant to antibiotics, as they have specific antimicrobial agents and, therefore, could be used to treat numerous infections, thereby contributing to reducing existing bacterial resistance.

1.2 Extracts

Traditional medicine has been accepted as an alternative form of health care. The ever-increasing microbiological resistance to available antibiotics has led researchers to investigate the antimicrobial activity of medicinal plants. Numerous extracts from different plants of the Myrtaceae family have been tested due to their antimicrobial activities, as their antimicrobial agents are increasingly potent against MDR bacteria. Therefore, medicinal plants and extracts from such plants are often recognized as a source of new drugs and complementary medicines for synthetic drugs and their versatile applications against microorganisms that cause respiratory tract infections.

Natural extracts are chemical compounds with biological activities from parts of medicinal plants (e.g., leaves, stems, fruits, and roots). These extracts have important biological properties, such as antioxidant, antifungal, antibacterial, and antiparasitic activity (Chakraborty et al. 2014; Njimoh et al. 2015). Multiple studies have analyzed chemical compounds and the antibacterial activity of extracts from different Myrtaceae family plants (Tab. S2, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;).

1.2.1 Genus Syzygium

Syzygium cumini (L.) Skeels, also commonly known as “jambolão,” plum java, and black plum, is native to tropical Asia, mainly India (Singh et al. 2016). Singh et al. (2016) evaluated the ethanolic extract of S. cumini and via high-performance liquid chromatography (HPLC) and found various phenolic compounds, namely: caffeic acid (65.6 mg mL^-1), gallic acid (41.4 mg mL^-1), synaptic acid (21.3 mg mL^-1), delphinidin (20.2 mg mL^-1), and quercetin acid (14.9 mg mL^-1). Analysis of the antibacterial activity of the extract against pathogenic strains revealed MICs between 0.5 and 2 mg mL^-1 against S. aureus (MTCC-740), K. pneumoniae (MTCC-109), and an MRSA isolate (Tab. S2, available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;). The S. cumini extract showed greater inhibitory potential, with MIC equal to 0.5 mg mL^-1 compared to the reference strain of S. aureus, while for the other bacteria, it reached a MIC of 2 mg mL^-1.

Panda et al. (2020) investigated the antibacterial activity of a Syzygium praecox (Roxb.) Rathakr. & N.C. Nair extract prepared with the leaves of the plant and acetone as a solvent and found terpenoids and alkaloids as the major phytochemicals. Nonetheless, this extract could not inhibit Staphylococcus MDR isolates and S. aureus strain ATCC 6538.

1.2.2 Genus Eucalyptus

Moradi et al. (2020) investigated the antibacterial effect of an extract of S. aromaticum and Eucalyptus camadulensis Dehnh. against P. aeruginosa (isolated from a patient with cystic fibrosis) and obtained bactericidal activity with MIC/MBC of 0.78/6.25 and 0.39/3.1 mg mL^-1, respectively.

1.2.3 Genus Myrtus

Myrtus communis L. is native to the Mediterranean region and other countries in the Middle East, such as Jordan, Iraq, and Saudi Arabia (Mir et al. 2020). Mir et al. (2020) identified, in the ethanolic extract of M. communis leaves, 50 constituents via GC-MS, the dominant compounds being 1.1.8a-trimethylocta-hydro-2.6-naphthalenedione (27.6%), pyrogallol (9.1%), and 1.8-cineole (3.9%). The antibacterial effect of the extract was evaluated against P. aeruginosa ATCC 9027 and isolates of S. aureus and K. pneumoniae, in which the standard strain tested and K. pneumoniae were resistant to the extract; only the isolate of S. aureus was inhibited (MIC of 9.7 µg mL^-1). In addition, the authors analyzed the MICs for several antimicrobials (colistin, vancomycin, tetracycline, and levofloxacin) alone and combined with the ethanolic extract of M. communis leaves, finding a MIC of 0.61 µg mL^-1 from the plant extract against S. aureus.

1.2.4 Genus Eugenia

Eugenia brasiliensis Lam. is popularly known as “grumixama,” “grumixameira,” and “Brazilian cherry”; this species has several varieties, although the most common is the yellow fruit (Silva et al. 2014; Teixeira et al. 2015). In one study, the ethanol extract of E. brasiliensis had a content of total phenolic compounds of 389.88 ± 3.48 mg of GAE/g, and in the LC-MS/MS, catechins, ellagitannins, flavonoids, and anthocyanins were identified (Lazarini et al. 2018). The E. brasiliensis extract showed a better antibacterial effect against S. aureus ATCC 25923 (MIC of 62.5 µg mL^-1) than MRSA ATCC 33591, and P. aeruginosa ATCC 27853 obtained a MIC of 250 µg mL^-1; the extract proved to be bactericidal for all microorganisms tested, with an MBC of 500 µg mL^-1. This extract did not present toxic effects on Galleria mellonella larvae at doses of 0.025 g/kg; therefore, the ethanol extract of E. brasiliensis should be further investigated for its safety in therapeutic uses, as natives have described it being effective in treating many diseases, including inflammatory and infectious diseases (Lazarini et al. 2018; Pietrovski et al. 2010; Silva et al. 2014).

Ramhit et al. (2018) researched extracts of plants endemic to Mauritania (Africa). The extracts of Eugenia elliptica Lam., Eugenia orbiculate Lam., and Eugenia tinifolia Lam. demonstrated significant differences in phenolic compounds, flavonoids, and proanthocyanidins. In the chemical characterization by HPLC, two flavonoids were found in E. tinifolia (kaempferol and quercetin) and only one in E. orbiculata (quercetin), as well as the polyphenol epigallocatechin. The authors noted that all the extracts had activity against the tested microorganisms in the antibacterial assays. The three extracts of the genus Eugenia presented a MIC of 19.5 μg of fresh weight (FW) mL^-1 against P. aeruginosa ATCC 27853. When tested against Klebsiella oxytoca ATCC 43086, this bacterium was more sensitive to E. orbiculata extracts (MIC = 4.9 μg FW mL^-1) and E. tinifolia (MIC = 9.7 μg FW mL^-1). The extracts showed MIC lower than at least one tested antibiotic (amoxicillin, chloramphenicol, and tetracycline) against the microorganisms. The difference in the effect of extracts and conventional antimicrobials may be in the penetrating power and levels of active compounds that interfere with the bacteria, which can lead to death (Ramhit et al. 2018).

1.2.5 Genus Campomanesia

Campomanesia adamantium (Cambess.) O. Berg is a plant in Brazil, native to the Cerrado biome, and popularly known as “guabiroba-do-campo” (Lima et al. 2011). Sá et al. (2018) evaluated the antimicrobial activity of several C. adamantium extracts, including crude ethanolic extract, hexane (HF), dichloromethane, ethyl acetate, and aqueous extracts. The HF extract was fractionated, resulting in fractions HF1, HF2/2, HF2/6, and HF9/3/1/2/1, which were analyzed by GC-MS. Caryophyllene oxides (HF1), isoaromadendrene (HF2/2), octadecanoic acid (HF2/6), and cubenol (HF9/3/1/2/1) were the chemical compounds found. All extracts tested showed antibacterial activity. Of all the extracts evaluated, HF had the best activity against S. aureus ATCC 6538 (MIC = 31.25 µg mL^-1). Afterward, the MIC for S. aureus ATCC 25923 was 62.5 µg mL^-1; for the clinical isolate of P. aeruginosa SPM1, MIC = 500 µg mL^-1. The other extracts obtained higher MIC, including when tested against K. pneumoniae ATCC 700603 (MIC >1000 µg mL^-1), in which the extract was less active.

1.2.6 Genus Callistemon

Callistemon citrinus (Curtis) Skeels is popularly known as bottlebrush and is widely distributed in Australia, South America, and tropical Asia, although it can also be found in other regions around the world (Oyedeji et al. 2009). Shehabeldine et al. (2020) evaluated the crude extract of C. citrinus against MRSA ATCC 33591 and MSSA ATCC 25923 and found a MIC of 125 and 62.5 µg mL^-1, respectively, while both presented MBC of 250 µg mL^-1. However, the MIC revealed bacteriostatic activity for the crude extract against MSSA and bactericidal activity against MRSA (Shehabeldine et al. 2020).

1.2.7 Genus Psidium

The species Psidium guayaquilense Landrum & Cornejo and Psidium rostratum Mc Vaugh (also known as “guayabas”) come from Ecuador. These species were evaluated by María et al. (2018), who conducted quantification tests of the total phenolic compounds; they found 941.97 ± 30.69 mg of GAE/g of dry extracts for the P. guayaquilense ethanolic extract and 591.34 ± 24.31 mg of GAE/g of dry extracts for the P. rostratum extract. Regarding antibacterial activity, both extracts were effective against S. aureus ATCC 25923, with a MIC of 50 µg mL^-1.

Within the genus Psidium is the species P. guajava L. (guava). Valle et al. (2015) evaluated ethanolic extracts of this species in the Philippines and observed antibacterial effects against S. aureus ATCC 25923, P. aeruginosa ATCC 27853, K. pneumoniae ATCC BAA-1705, K. pneumoniae carbapenem-resistant, K. pneumoniae producer of extended-spectrum β-lactamase (ESβL), A. baumannii metallo-β-lactamase (MβL), P. aeruginosa MβL, MRSA 1 (wound isolate), MRSA 2 (wound isolate), MRSA 3 (blood isolate), and MRSA 4 (sputum isolate). In the disc diffusion method, only MRSA isolates were sensitive to the extract, and the inhibition halos ranged from 13 to 18 mm (Valle et al. 2015). In contrast, Chakraborty et al. (2018) analyzed the effect of a P. guajava ethanolic extract against ten clinical MRSA isolates and ten non-clinical MRSA isolates and found that the inhibition zone in a non-clinical MRSA culture was 29.69 ± 0.78 mm compared to 24.73 ± 0.55 mm for clinical MRSA isolates. The results of Valle et al. (2015) for the antibacterial activity using the guava ethanolic extract only showed action against S. aureus ATCC 25923 and against all MRSA. The extract did not present any activity against the other microorganisms. The lowest MIC (625 µg mL^-1) were found against MRSA 1 and 4. The extract tested against MRSA 4 was bactericidal at the same concentration of MIC; however, for MRSA 1, it needed a higher concentration (2500 µg mL^-1) to inhibit bacterial growth (Valle et al. 2015).

Fu et al. (2016) tested the phenolic compounds in the methanolic extract of P. guava and found six constituents: catechin (391.93 ± 15.08 mg kg^-1), quercetin (122.23 ± 10.14 mg kg^-1), gallic acid (99.15 ± 1.62 mg kg^-1), epicatechin (58.43 ± 4.70 mg kg^-1), luteolin (51.39 ± 3 mg kg^-1), and kaempferol (38.06 ± 2.00 mg kg^-1). When testing the methanolic extract of guava against microorganisms, the best results were obtained against P. aeruginosa ATCC 27853, as it reached lower MIC and MBC (312.5/312.5 mg mL^-1) compared to S. aureus CMCC(B)26003 (1250/2500 mg mL^-1). The authors evaluated the compounds found in the extract separately and observed that the polyphenol catechin, the major constituent in the extract, presented MIC and MBC of 1.25 mg mL^-1 against S. aureus and 2.50 mg mL^-1 against P. aeruginosa. When tested separately, the compound with the best antibacterial activity was gallic acid against S. aureus, with activity at 0.63 mg mL^-1 (MIC/MBC), a constituent also found in the P. guava extract (Fu et al. 2016).

Psidium cattleianum Sabine is popularly known as “araçá,” “araçá-do-mato,” “araçá-do-campo,” “yellow araçá,” “red araçá,” “araçazeiro,” and “araçazeiro-da-praia” (Coradin et al. 2011; Raseira et al. 2004). This plant originated in Brazil and can be found in Bahia, Rio Grande do Sul, and Santa Catarina States (Biegelmeyer et al. 2011). Many studies have demonstrated the use of P. cattleianum in various areas (Dacoreggio et al. 2019; Medina et al. 2011; Scur et al. 2016). However, few studies have evaluated P. cattleianum, especially against bacteria associated with respiratory infections (i.e., MDR).

Dacoreggio et al. (2019) obtained aqueous extracts of P. cattleianum leaves harvested in winter and summer. The researchers employed water + ultrasound (WU) extraction and water + enzyme - cellulase complex (WE) extraction. Regarding the number of total phenolics, there was no statistically significant difference (p < 0.05), considering how the extracts were obtained; nonetheless, the phenolic content presented differences in terms of the season in which the leaves were collected. The results in determining the total phenolic content were expressed as gallic acid equivalents (GAE) per g of dry vegetal material. Values of 101 mg of GAE g^-1 (WU) were observed in the extract that the leaves were harvested in the summer and a higher content of phenolic compounds in those harvested in the winter (WU - 144 mg of GAE g^-1). The same was observed in the WE extract; in the summer, the authors found 121 mg of GAE g^-1, while in the winter, 123 mg of GAE g^-1 of phenolic compounds. The outliers of the number of phenolic compounds in each extract can vary depending on several environmental factors, such as the temperature difference in the seasons (Dacoreggio et al. 2019).

When testing the antibacterial activity of the aqueous extract of P. cattleianum, the authors obtained MIC ranging from 12.6 to 18 μg mL^-1 against S. aureus. The two extracts showed lower MIC than the extracts made with leaves collected in the summer season (WU = 12.6 μg mL^-1 and WE = 15.1 μg mL^-1) (Dacoreggio et al. 2019).

1.3 Formulations containing Myrtaceae and nanoparticles

Nanotechnology has been applied in various areas. As a delivery system, it has been investigated to contribute to the control and release of drugs, improve the effectiveness and selectivity of drugs, and assist in treating infectious diseases (Flores et al. 2011; Gupta & Gupta 2005). Table 3 (available on supplementary material <https://doi.org/10.6084/m9.figshare.22318294.v1>;) shows nanoparticles synthesized with extracts from different plant species of the Myrtaceae family.

Asghar et al. (2020) investigated the antibacterial activity of synthesizing chitosan functionalized silver nanoparticles using ethanolic bud extract of S. aromaticum against resistant microorganisms, such as vancomycin-resistant S. aureus (VRSA) LT 4312 and MRSA LT 0531, and found a MIC of 64 µg mL^-1. Nickel oxide nanoparticles (NiO-NPs) have also been suggested as antibacterial agents; Saleem et al. (2017) synthesized NiO-NPs with Eucalyptus globulus leaf extracts (ELE), presenting an average NiO-NP size of 19 nm. The antimicrobial activity of the NiO-NPs synthesized was tested with 1 mM NiNO3 and ELE with distilled water (1:8 v/v) using diffusion technique against the clinical isolate of P. aeruginosa ESβL (48 and 64), MSSA (MS-2 and MS-6), and MRSA (MR-10 and MR-31), in which they found zones of inhibition that varied between 13-15 mm. In contrast, the MIC presented against all microorganisms was 0.8 mg mL^-1 and MBC was 1.6 mg mL^-1. In addition, the combination of the nanoparticle and ELE inhibited biofilm formation depending on the tested dose. The antibiofilm concentrations tested were 0, 0.1, 0.2, 0.4, 0.8, and 1.6 mg mL^-1 of NiO-NPs. The best results were obtained for the MRSA isolate (32, 62, 72, 73, 76, and 83% inhibition, respectively). The results of Saleem et al. (2017) are positive, allowing NiO-NPs associated with E. globulus extract to be applied against bacterial infections, protecting human health from pathogenic microorganisms.

Although some studies have already investigated the green synthesis of silver nanoparticles, there is currently no alternative treatment for infection by MDR microorganisms. Wintachai et al. (2019) investigated the potential of silver nanoparticles synthesized with ethanolic extract of E. critriodora leaves as an inhibitor of MDR A. baumannii infection. The spherical size of the nanoparticle ranged from 8 to 15 nm. Antibacterial assays (MIC) were performed against clinical isolates of MDR A. baumannii (n = 10), in which the MIC and MBC varied from 0.05 to 0.18 μg mL^-1 and 0.36 to 0.72 μg mL^-1, respectively. A reference strain of A. baumannii ATCC 19606 was used, which obtained MIC and MBC of 0.09 and 0.36 μg mL^-1. The antibiofilm activity of the silver nanoparticle associated with E. critriodora extract was analyzed against five clinical isolates of A. baumannii MDR plus the standard strain in parallel with colistin. When testing 1/8 to 1/2 of the MIC (0.012-0.045 μg mL^-1) of silver nanoparticles, the best result for the reduction in biofilm formation was the one presented in 1/8 MIC (0.012 μg mL^-1). The silver nanoparticle synthesized with the E. critriodora extract did not show significant cytotoxicity at the maximum concentration of 0.72 μg mL^-1 when tested against the human lung epithelial cell line (A549). The authors also analyzed that the clinical isolates of A. baumannii MDR in A549 cells were sensitive when treated with concentrations varying from 1/8 to 1/2 MIC (0.012-0.045 μg mL^-1). After checking the results, nanoparticles synthesized with the ethanolic extract of E. critriodora may be a potential alternative therapy to reduce respiratory infections, such as those caused by MDR A. baumannii (Wintachai et al. 2019).

Hashemi et al. (2020) prepared iron (ZVINPs) and silver (AgNPs) nanoparticles, in which the biosynthesis of both was using an aqueous extract of Feijoa sellowiana fruit. Through HPLC, five phenolic acids were detected in the extract: catechin 1 (188.5 mg g^-1 of extract), gallic acid 2 (18.5 mg g^-1 of extract), caffeic acid 3 (3.2 mg g^-1 of extract), rutin 4 (15.8 mg g^-1 of extract), and p-coumaric acid 5 (4.7 mg g^-1 of extract). The authors investigated the antibacterial activity of the nanoparticles against pathogenic bacteria (S. aureus ATCC 29213, A. baumannii ATCC 29606, K. pneumonia ATCC 700603, and P. aeruginosa ATCC 27853) and clinical isolates from the same species. The tested concentrations of each nanoparticle ranged from 125 to 0.25 μg mL^-1 of AgNPs and from 30 to 0.15 μg mL^-1 of ZVINPs. The ZVINPs showed the best antibacterial potential against three standard strains tested (A. baumannii ATCC 29606, K. pneumonia ATCC 700603, and P. aeruginosa ATCC 27853); for S. aureus ATCC 29213, the AgNPs had a more significant effect, resulting in a MIC of 2 μg mL^-1. Both nanoparticles proved bactericidal against the strains evaluated (Hashemi et al. 2020).

Hashemi et al. (2020) also tested the antibacterial activity of nanoparticles against clinical isolates of S. aureus, A. baumannii, K. pneumoniae, and P. aeruginosa, in which AgNPs showed better activity against A. baumannii (3.5 μg mL^-1) and S. aureus (4 μg mL^-1). In contrast, ZVINPs against P. aeruginosa and K. pneumoniae presented a MIC of 15 μg mL^-1 for both bacteria. The two nanoparticles were bactericidal, although the lowest concentrations of MBC found were for the ZVINPs. The mechanism of action of silver nanoparticles synthesized with the F. sellowiana extract is due to the presence of phenolic compounds in the extract reacting with the silver nanoparticles and forming a complex, fighting microorganisms (Ebrahimzadeh et al. 2019; Hashemi et al. 2020).

Ali et al. (2015) performed the green synthesis of AgNPs with an aqueous ELE by developing a solution with both products (1:4 v/v) and irradiating them with microwaves. The ELEAgNPs were approximately 1.9-4.3 nm in size with microwave treatment and 5-25 nm without treatment. The ELEAgNPs were evaluated for antibacterial activity against P. aeruginosa ESβL, MRSA (MR-6), and MSSA (MS-6). In the diffusion test, when ELEAgNPs were tested, the inhibition zones ranged from 19 to 21 mm compared to the values tested only with ELE (8-10 mm). The MIC and MBC with ELEAgNPs against MRSA were 27 and 30 μg mL^-1 and against MSSA were 30 and 33 μg mL^-1, while for P. aeruginosa ESβL, were 27 and 36 μg mL^-1. The authors performed antibiofilm activity with a concentration of 30 μg mL^-1, showing 82 ± 3% and 81 ± 5% biofilm inhibition against S. aureus and P. aeruginosa, respectively. This inhibition can occur due to the polyphenol compounds in the chemical characterization of the E. globulus leaf extract, which can capture the iron in the medium, killing the microorganisms (Ali et al. 2015).

The formulation of iron nanoparticles (FeNP) synthesized with an aqueous extract of E. robusta leaves with various concentrations of iron salt in the proportion of 1:1 was evaluated by Vitta et al. (2020). As for the quantification of phenolic and flavonoid compounds, E. robusta extract showed 158.47 ± 0.64 mg gallic acid (GAE)/g extract and 131.12 ± 4.49 (mg quercetin (QE)/g extract, respectively, while FeNP showed 98.21 ± 10.34 mg GAE/g and 40.54 ± 6.87 mg QE/g, respectively. The antibacterial activity through the agar diffusion method evaluated the FeNP obtained under various forms of synthesis in the following concentrations (FeNP I = 0.01 g mL^-1 extract + 1 mM [Fe]; FeNP II = 0.01 g mL^-1 extract + 5 mMe [Fe]; FeNP III = 0.005 g mL^-1 + 0.005 mM [Fe]) against P. aeruginosa and S. aureus, and as the size of the nanoparticle decreased, increased the size of the inhibition halos. It is believed that the chemical composition of E. robusta extract contributed to the antibacterial potential, in addition to the fact that the size of the nanoparticle interfered with the mechanism of action because the smaller the particle, the greater the power of penetration into the bacteria. Thus, nanoparticles are promising alternatives for application as antibacterial agents in clinical practice(Vitta et al. 2020).

Given the growing problem of bacterial resistance with each passing year, it is becoming increasingly difficult to contain the microorganisms that cause respiratory tract infections that eventually become MDR. One of the leading causes is the indiscriminate and excessive use of conventional drugs the market offers, thereby emphasizing the need and urgency to develop new antimicrobials that serve as a strategy for conventional antibiotics, enabling researchers and industry professionals to control and eliminate these microorganisms (especially MDR bacteria), or even antibacterial agents that enhance the action of existing drugs.

This review provided studies performed in recent years with plants of the Myrtaceae family, presenting their chemical composition and in vitro antibacterial activity against microorganisms that cause respiratory infection, including A. baumannii, S aureus, P. aeruginosa, H. influenzae, K. pneumoniae, and K. oxytoca. As for the chemical characterization, the essential oils found in most studies present terpenoid constituents, while research with Myrtaceae extracts showed phenolic compounds, especially phenolic acids, and flavonoids. Plants of this family have various constituents with antimicrobial activity and can be used to treat bacteria that cause respiratory infections. In addition, few clinical studies were conducted with plants of the Myrtaceae family and tested against pathogens involved in MDR respiratory infections. Hence, it is crucial to encourage the scientific community to continue seeking new and effective therapeutic agents so that they are applied clinically against the microorganisms that cause respiratory tract infections, as numerous studies have demonstrated the promising results of employing species of the Myrtaceae family.

Acknowledgements

The authors acknowledge the Coordination for the Improvement of Higher Education Personnel (CAPES) for granted at a scholarship, grant 001. The publication of this paper was partially supported by PRPPGI/UFPel and CAPES. We would also like to thank Atlas Assessoria Linguística for language editing.

• See supplementary material at <https://doi.org/10.6084/m9.figshare.22318294.v1>

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Area Editor: Dr. Leopoldo Baratto

Publication Dates

• Publication in this collection
  29 May 2023
• Date of issue
  2023

History

• Received
  14 July 2022
• Accepted
  06 Nov 2022