Latin American Plants against Microorganisms

The constant emergence of severe health threats, such as antibacterial resistance or highly transmissible viruses, necessitates the investigation of novel therapeutic approaches for discovering and developing new antimicrobials, which will be critical in combating resistance and ensuring available options. Due to the richness and structural variety of natural compounds, techniques centered on obtaining novel active principles from natural sources have yielded promising results. This review describes natural products and extracts from Latin America with antimicrobial activity against multidrug-resistant strains, as well as classes and subclasses of plant secondary metabolites with antimicrobial activity and the structures of promising compounds for combating drug-resistant pathogenic microbes. The main mechanisms of action of the plant antimicrobial compounds found in medicinal plants are discussed, and extracts of plants with activity against pathogenic fungi and antiviral properties and their possible mechanisms of action are also summarized. For example, the secondary metabolites obtained from Isatis indigotica that show activity against SARS-CoV are aloe-emodin, β-sitosterol, hesperetin, indigo, and sinigrin. The structures of the plant antimicrobial compounds found in medicinal plants from Latin America are discussed. Most relevant studies, reviewed in the present work, have focused on evaluating different types of extracts with several classes and subclasses of secondary metabolites with antimicrobial activity. More studies on structure–activity relationships are needed.


Introduction
Infectious diseases are a significant source of public health issues.Despite breakthroughs in creating and manufacturing antivirals and antibiotics, bacteria, viruses, and other microorganisms continue to kill millions of people each year.
Antimicrobial resistance is a severe and developing clinical issue that has reduced the therapeutic effectiveness of conventional antibiotics and narrowed the treatment choices for bacterial infections.Antibiotic-resistant bacteria are generally difficult to treat due to reduced membrane penetration, efflux pump overexpression, target site shifting, inactive subpopulations, biofilm growth, and enzymatic destruction.Resistant bacteria are strains resistant to several medicines, resulting in increased infections [1].
Many bacteria may infect and live in their hosts for extended periods.This might be related to host immunosuppression, pathogen immune evasion, and/or inadequate drug clearance.Bacteria that are resistant or tolerant to antibiotics can survive treatment.Persistent bacteria are a transiently antibiotic-tolerant subset of bacterial cells that grow slowly Plants 2023, 12, 3997 2 of 31 or cease developing but can resume proliferation after exposure to fatal stress.Persistent cell production creates phenotypic variation within a bacterial population, significantly enhancing the odds of effectively responding to environmental change.The existence of resistant cells can lead to the emergence and recurrence of chronic bacterial infections and an increased risk of antibiotic resistance [2].
Emerging viral infections, on the other hand, continue to be a severe concern for worldwide public health.In 1997, it was revealed that a highly virulent avian influenza A (H5N1) virus may be transferred directly from poultry to people, in contrast to previously known human-to-human and livestock-to-human modes of transmission, raising severe fears about a probable influenza pandemic.Several additional avian influenza A virus subtypes (H7N9, H9N2, and H7N3) have also been linked to human sickness, increasing concerns that all influenza A virus subtypes circulating in domestic poultry and cattle in the wild might transmit to people and cause pandemics.
The most recent viral pneumonia epidemic, which began in mid-December 2019 (COVID-19) in Wuhan, China, and has spread swiftly throughout the world, is a stark reminder of our vulnerability to new viral illnesses.Tens of thousands of people are currently infected with SARS-CoV-2 [3].
In the case of fungus, it is believed that roughly 5 million species are extensively ubiquitous in the environment, of which approximately 300 can cause infections in people.However, only 20-25 are commonly seen in the clinic and are the cause of sick patients.Patients with HIV, organ transplant recipients, or those undergoing chemotherapy are examples of such people.The most frequent fungal diseases are Candida spp., Cryptococcus spp., Aspergillus spp., and Pneumocystis spp., which cause around 2 million illnesses and 1 million deaths yearly [4].
Because of the above, it is critical to enhance ways of treating infection-related disorders, preventing their spread, and filling the medicine shortage in order to alleviate this public health crisis.In an era of falling antimicrobial efficacy and the fast growth of antibacterial resistance, it is critical to develop novel therapies and tactics based on discovering new active components.
The exploration of active chemicals of natural origin is such potential methodology.Natural goods have served as a source of and the inspiration for many of the pharmaceuticals available today.Although numbers vary depending on the definition of what is deemed a medicine produced from a natural substance, it is reasonable to conclude that, today, natural products are the source of 25% to 50% of the pharmaceuticals on the market.The proportion is much more significant in the case of anti-cancer and anti-infective agents, with over two-thirds of such drugs originating from natural sources.Several recent reviews emphasize the importance of natural products in drug discovery.Many medicines in clinical use are derived from natural products that originated from microbial species, particularly in anti-infectives.However, drugs derived from plants have also made significant contributions.Humanity would undoubtedly be immeasurably poorer without plant-derived natural medicines such as morphine, vinblastine, vincristine, and quinine [5].
We provide a critical review of current research on natural product antibacterial activity and the discovery and classification of secondary metabolites of plants with antimicrobial activity, each with a distinct mechanism of action.The mechanisms of action of natural antifungal agents are also discussed, as are the potential antiviral mechanisms of biocompounds, which include viral replication inhibition through polymerases, proteases, integrases, fusion molecules, and cell membrane adhesion.
The Latin American plants presented in this review were selected from papers published in the last 20 years using databases such as SciFinder ® , ScienceDirect ® , Scopus ® , PubMed ® , PLOS, NATURE, and Google Scholar ® .For the article search, the keywords "antimicrobial resistance", "antibiotic resistance intrinsic", "antibiotic resistance adaptive", "antibiotic resistance acquired", "antibiotic resistance mechanisms", "antimicrobial activity of medicinal plants multidrug resistant bacteria", "plant extract antimicrobial activity", "plant extract multidrug resistant strains", "plant extract antibiotic resistance", Plants 2023, 12, 3997 3 of 31 "pathogenic fungi AND bioactive compounds", "plant extracts AND pathogenic fungi", "secondary metabolites AND fungal infections", "drug resistance AND fungi", "secondary metabolites against fungal infections" and "pathogenic fungi AND drug resistance" were used.The search in each database returned the following results: SciFinder ® (112 articles), ScienceDirect ® (556 articles), Scopus ® (1157 articles), PubMed ® (2365 articles), PLOS (552 articles), NATURE (409 articles), and Google Scholar ® (6354 articles).After a preliminary filter to collect only Latin American plants, 3827 articles were collected; of these, articles discussing non-specific antimicrobial (antibiotic, antifungal, and antiviral) activity were discarded.Only original papers and those published from 2003 to 2023 were considered for data collection.

Antimicrobial Resistance
As COVID-19 rages, the antimicrobial resistance (AMR) epidemic continues in the background.AMR causes recurrent microbe (viruses, bacteria, and fungi) infections that lengthen hospital stays and result in preventable deaths.It is estimated that 4.95 million people died due to AMR in 2019 and that by 2050, there will be 10 million annual deaths due to antimicrobial resistance.Two factors primarily cause antimicrobial resistance.The first is the overuse of antimicrobials, which exposes microbes to them regularly, increasing their chances of developing resistance.The second issue is that few new antimicrobial drugs are being developed to replace ineffective ones due to rising drug resistance [6,7].
Compared to non-resistant forms, resistant bacteria are two times more likely to develop into a serious health problem and are three times more likely to lead to death [8,9].Resistance to first-line antibiotics, such as fluoroquinolones and lactam antibiotics, is responsible for more than two-thirds of AMR-related deaths (carbapenems, cephalosporins, and penicillins).People with low incomes are disproportionately affected by AMR because they have limited access to more expensive second-line antibiotics that may be effective when first-line drugs fail.Physicians should avoid inappropriate antibiotic therapy when, for example, the illness has a viral origin [6,10,11].
There are different mechanisms of resistance to antibiotics (Figure 1).Bacteria produce enzymes that can destroy or alter the structure of the drug, causing the drug to lose its activity during enzymatic inactivation.Drug-inactivating enzymes are classified into three types: hydrolase (primarily lactamase), passivating enzymes (aminoglycoside-inactivating enzyme, chloramphenicol acetyltransferase, and erythromycin esterase), and modifying enzymes (aminoglycoside-modifying enzyme).Similarly, changing the target to which the drug is directed ensures that the antibiotic binds appropriately to the bacteria.This mechanism is primarily seen in Gram-positive bacteria with drug resistance and polymyxin resistance.Changes in outer membrane permeability that result in channel alteration or decreased expression make the bacteria less sensitive.In the drug efflux pump, when the drug is removed from the bacterial cytoplasm, the concentration is much lower than is required for it to exhibit activity, resulting in drug resistance.This process requires energy and works with various antibiotics [7,[12][13][14].

Natural Products and Plant Extracts with Antimicrobial Activity against MDR Strains
Multidrug resistance (MDR) is a major cause of human suffering because it undermines doctor-patient trust, resulting in massive economic losses.In this world of microbe-man cohabitation, the survival of the human species will be compromised in the absence of health-giving microbes, and there will be no way to avoid the emergence of MDR superbugs.Throughout history, the isolation and identification of biologically active compounds and molecules from nature have resulted in the discovery of new therapeutics, advancing the health and pharmaceutical industries.Phytochemicals are used in the research and development of the pharmaceutical industry as a source of new molecules, leading to the development of novel drugs [15,16].
As shown in Table 1, several classes and subclasses of secondary metabolites (Figure 2) have been isolated from plants with antimicrobial activity, each with a different mechanism of action.This table shows that, depending on the compound class, they share the same kind of mechanism of action.
Regarding essential oils, the essential oil of rosemary (Rosmarinus officinalis) was found to have antibacterial activity against three types of MDR acne-causing bacteria: Staphylococcus aureus, Staphylococcus epidermidis, and Cutibacterium acnes [17].Similarly, volatile oils extracted from cinnamon (Cinnamomum verum) and tree basil (Ocimum gratissimum) had potent bactericidal activity against MDR A. baumannii bacteria [18].
Terminalia bellirica fruits were studied, and it was discovered that the aqueous and methanol extracts had antibacterial activity against all strains of MRSA (Methicillin-resistant Staphylococcus aureus), MDR Acinetobacter spp., and MDR P. aeruginosa [19].
The aqueous, hexane, and ethanol extracts of Punica granatum peel demonstrated antibacterial activity against MDR pathogens such as P. aeruginosa and A. baumannii.Valoneic acid dilactone (aqueous fractions), Hexoside (ethanol fractions), and Coumaric acid (hexane fractions) were discovered to be bioactive compounds [18].Ethanolic extracts of Azadirachta indica, Allium sativum, and Syzygium cumini were found to have anti-MDR-Candida spp activity.According to a phytochemical analysis of ethanolic plant extracts, all

Natural Products and Plant Extracts with Antimicrobial Activity against MDR Strains
Multidrug resistance (MDR) is a major cause of human suffering because it undermines doctor-patient trust, resulting in massive economic losses.In this world of microbe-man cohabitation, the survival of the human species will be compromised in the absence of health-giving microbes, and there will be no way to avoid the emergence of MDR superbugs.Throughout history, the isolation and identification of biologically active compounds and molecules from nature have resulted in the discovery of new therapeutics, advancing the health and pharmaceutical industries.Phytochemicals are used in the research and development of the pharmaceutical industry as a source of new molecules, leading to the development of novel drugs [15,16].
As shown in Table 1, several classes and subclasses of secondary metabolites (Figure 2) have been isolated from plants with antimicrobial activity, each with a different mechanism of action.This table shows that, depending on the compound class, they share the same kind of mechanism of action.
Regarding essential oils, the essential oil of rosemary (Rosmarinus officinalis) was found to have antibacterial activity against three types of MDR acne-causing bacteria: Staphylococcus aureus, Staphylococcus epidermidis, and Cutibacterium acnes [17].Similarly, volatile oils extracted from cinnamon (Cinnamomum verum) and tree basil (Ocimum gratissimum) had potent bactericidal activity against MDR A. baumannii bacteria [18].
Terminalia bellirica fruits were studied, and it was discovered that the aqueous and methanol extracts had antibacterial activity against all strains of MRSA (Methicillin-resistant Staphylococcus aureus), MDR Acinetobacter spp., and MDR P. aeruginosa [19].
The aqueous, hexane, and ethanol extracts of Punica granatum peel demonstrated antibacterial activity against MDR pathogens such as P. aeruginosa and A. baumannii.Valoneic acid dilactone (aqueous fractions), Hexoside (ethanol fractions), and Coumaric acid (hexane fractions) were discovered to be bioactive compounds [18].Ethanolic extracts of Azadirachta indica, Allium sativum, and Syzygium cumini were found to have anti-MDR-Candida spp.activity.According to a phytochemical analysis of ethanolic plant extracts, all the plants studied contained alkaloids, flavonoids, glycosides, phenols, tannins, and saponins [20].Aside from the plant extracts mentioned above, various plant compounds (Figure 3) with anti-MDR bacteria activity have already been identified.Table 2 lists these compounds, as well as the biological effects they have on specific strains.
Because of the severe problem of MDR properties in microbes, the discovery of alternative drugs from natural products should be one of the primary goals of current research.Understanding the nature of pathogenic microbes, recognizing biofilm formation and  1.
Aside from the plant extracts mentioned above, various plant compounds (Figure 3) with anti-MDR bacteria activity have already been identified.Table 2 lists these compounds, as well as the biological effects they have on specific strains.
Because of the severe problem of MDR properties in microbes, the discovery of alternative drugs from natural products should be one of the primary goals of current research.Understanding the nature of pathogenic microbes, recognizing biofilm formation and architectural scheme, and employing cross-disciplinary techniques are thus critical for discovering new potent and novel drugs.Binds to proteins, bind to adhesins, enzyme inhibition, substrate deprivation, complex with the cell wall, membrane disruption, metal ion complexation. [27] Coumarins Warfarin (13)

Pathogenic Fungi for Human
Fungi are eukaryotic organisms widely distributed across the planet, with more than 700,000 species classified [57]; however, it is estimated that there may be more than 1 million species in existence [58].Despite these data, the number of fungi that can affect other species is minimal, with less than 0.1% being of medical importance to humans, and less than 50 species being identified as pathogenic fungi.In recent years, fungi adapted to modified ecosystems have significantly impacted human health, as they tend to infect plants and their metabolism, negatively affecting the food web [59,60].
Mycoses are usually superficial, cutaneous, systemic, or opportunistic.A worldwide risk factor is immunosuppression; however, the microbiome imbalance caused by antibiotics must be considered, as it can lead to an even more severe infection [61,62].It is widely thought that most mycoses are opportunistic.It is extremely important to take into account that mycosis can be considered dangerous due to the entry of several fungi, with cosmopolitan genera such as Candida, Cryptococcus, and Aspergillus being prevalent [63][64][65], while creating invasive fungal infections (IFIs) that cause high mortality rates worldwide [60,66,67].

Mechanism of Action and Drug-Resistance of Pathogenic Fungi
Pathogenic fungi create complex signaling cascades that depend on the host and environment [68].A 2017 review points out the importance of recognizing the pathways involved in fungal pathogenicity and identifying opportunity areas to create better antibiotics [69], even if knowing these factors would make it impossible to create efficient vaccines [70,71].However, current antifungal drugs have different mechanisms of action (Table 3); the most common mechanisms are directed against the fungal cell wall or membrane, specifically against ergosterol or (1,3)-β-d-glucan biosynthesis, except for pyrimidines and orotomides that target crucial molecules in nucleic acid metabolism [72][73][74][75].

Pyrimidines (flucytosine)
Bind to cytosine permease, already in the nucleus, and generate fluorardilic acid, which is incorporated into the RNA, rendering it useless. [ Inhibit dihydroorotate dehydrogenase synthesis, preventing the synthesis of DNA and RNA.[76,77] Fosmanogepix Inhibits the enzyme Gwt1, responsible for glycosylphosphatidylinositol synthesis.[75] Just as bacteria generate drug resistance, so do fungi; this drug resistance can be described from a clinical point of view, referring to the worsening of an infection despite receiving adequate drug treatment.On the other hand, in the laboratory context, resistance is evaluated through a Minimum Inhibitory Concentration (MIC) assay to determine the growth of the pathogen at different concentrations of antibiotics [68,69,78].It is necessary to point out the concept of drug tolerance, which is considered as the fungus persistence on the substrate; however, its growth is slow due to multifactorial causes [79,80].

Latin American Plants with Antifungal Effects
Fungi drug resistance has created a worldwide clinical challenge, and treatment alternatives have been considered, such as including two or more antifungals for one treatment; however, this does not make a significant difference [81].This is why alternatives should be considered, such as using plant-derived compounds that can act via bypassing common metabolic pathways in fungal pathology.Table 4 summarizes the medicinal plant extracts with antifungal properties.

Medicinal Plant Antiviral Activity against Human-Infecting Viruses
In 2018, over 4400 virus species were classified into 122 families and 7535 [111] subfamilies.Human-infecting viruses include RNA viruses, DNA viruses, retroviruses, bare viruses, and virions, with RNA viruses being the most prevalent.Numerous medicinal plants contain compounds that inhibit the replication of viruses or enhance the immune system.Alkaloids, terpenes, flavonoids, numerous glucosides, and proteins have been recognized as phytochemicals; their metabolites include apigenin (29), kaempferol (34), and luteolin (25), in addition to the triterpenoids oleanolic acid (35) and ursolic acid (36) [112].
Table 5 summarizes the medicinal plant extracts and their possible mechanisms of action (Figure 4), while Table 6 discusses the medicinal plant biocompounds with antiviral properties (Figures 5-7).
Table 5 summarizes the medicinal plant extracts and their possible mechanisms of action (Figure 4), while Table 6 discusses the medicinal plant biocompounds with antiviral properties (Figures 5-7).

Antiviral-Active Extracts for Respiratory Infections
The leading cause of morbidity in humans is viral respiratory tract infections, with rhinovirus, influenza, respiratory syncytial virus (RSV), and human coronavirus having the most significant impact.

Antiviral-Active Extracts for Respiratory Infections
The leading cause of morbidity in humans is viral respiratory tract infections, with rhinovirus, influenza, respiratory syncytial virus (RSV), and human coronavirus having the most significant impact.
Eugenin ( 43) is a biocompound extracted from Geum japonicum and Syzygium aromaticum.Eugenin (43) inhibits the DNA polymerase of the Herpes simplex virus, which appears to be its mechanism of action.Also, it inhibits Herpes simplex virus activity in both Vero cells and mice [127].
Curcumin (33) is highly effective at reducing TPA-, butyrate-, and TGF-b-induced levels of BZLF1 mRNA and TPA-induced luciferase mRNA, indicating that it inhibits three main EBV pathways [135].
Apigenin (29) inhibits the expression of the EBV lytic proteins Zta, Rta, EAD, and DNase in B and epithelial cells.In addition, it decreases the number of EBV-reactivating cells detectable via immunofluorescence analysis.Additionally, apigenin (29) has been found to significantly reduce EBV virus production [136].6). Figure 6.Antiviral biological compounds (Table 6).

Activity against Epstein-Barr Virus
Epstein-Barr (EBV) is a herpes virus that affects 90 percent of the world's population and is linked to numerous immunological and neoplastic diseases.
The compounds sesamol (49) and resveratrol (2), along with sesame and sunflower essential oils, inhibit the early antigen activation in vitro of the Epstein-Barr virus [132].
Berberine ( 15) is an alkaloid derived from several medicinal plants (Cortidis rhizome, Coptis chinensis, and Barnerini vulgaris) that inhibits cell proliferation and induces apoptosis in Epstein-Barr virus-infected cells via the inhibition of p-STAT3 and the overexpression of EBNA1 [134].
Curcumin (33) is highly effective at reducing TPA-, butyrate-, and TGF-b-induced levels of BZLF1 mRNA and TPA-induced luciferase mRNA, indicating that it inhibits three main EBV pathways [135].
Apigenin (29) inhibits the expression of the EBV lytic proteins Zta, Rta, EAD, and DNase in B and epithelial cells.In addition, it decreases the number of EBV-reactivating cells detectable via immunofluorescence analysis.Additionally, apigenin (29) has been found to significantly reduce EBV virus production [136].
Glycyrrhizic acid (56) (18-GL or GL) possesses a wide range of antiviral activities, pharmacological effects, and sites of action.In vitro, GL (56) inhibits Epstein-Barr virus (EBV) infection by interfering with an early stage in the EBV replication cycle (possibly attachment or penetration) [137].
The flavonoid luteolin (25) inhibits EBV reactivation significantly.In EBV-positive epithelial and B cell lines, 25 inhibits the expression of EBV-lytic gene-encoded proteins.In addition, it decreases the number of EBV-reactivating cells detected via immunofluorescence and virion production.Moreover, 25 decreases the activities of the promoters of the immediate-early genes Zta (Zp) and Rta (Rp).It inhibits the activity of Sp1-luc, indicating that the disruption of Sp1 binding is involved in the mechanism of inhibition [138].

Anti-Cytomegalovirus Activities
Human cytomegalovirus (hCMV) is a pervasive herpesvirus that causes a latent infection that persists throughout the host's lifetime and can be reactivated when immunity is compromised.
Genistein (55) and baicalein (57) are antiviral flavonoids against HCMV.The primary mode of action of genistein's antiviral activity against HCMV is to inhibit the function of immediate-early proteins.Baicalein's antiviral activity against HCMV works primarily by inhibiting the kinase activity of EGFR to prevent viral entry [139].
Supplementation with piceatannol (58) inhibits the lytic changes caused by hCMV infection.In addition, piceatannol dose-dependently inhibits the expression of hCMV immediate-early (IE) and early (E) proteins and the replication of hCMV DNA [140].
Resveratrol (2) inhibits human cytomegalovirus DNA replication to undetectable levels during the second (late) phase of virus-induced phosphatidylinositol-3-kinase signaling and transcription factor activation [141].
Allitridin (59), a compound extracted from A. sativum, reduces the amount of viral DNA in cytomegalovirus-infected cells by inhibiting the transcription of the IE gene [142].
The Phyllanthus embolica aqueous extract inhibits hemagglutinin and viruses in infected cells [174].Catechin derived from Camellia sinensis inhibits both RNA synthesis and neuraminidase activity [175].
Echinacea extract is active against influenza A/B viruses (H3N2, H1N1, H5N1, H7N7, and S-OIV), Respiratory Syncytial Virus, and Herpes Simplex [177].On the other hand, it also induces the production of IL-6 and IL-8 (CXCL8) and other cytokines with antiviral properties [178].In a clinical trial, it was demonstrated to be as effective as oseltamivir in reducing influenza symptoms if administered at the onset of the disease [179].
On the other hand, the monoterpene aldehydes citral a (45) and citral b (46), from Melissa officinalis, exhibit synergistic activity with oseltamivir against the H9N2 influenza virus [180].
Wyde et al. [181] found that polyphenolic polymers derived from the Euphorbiaceae shrub are active in vitro against parainfluenza virus type 3, Respiratory Syncytial Virus, and influenza viruses.

Conclusions
The Latin American plant species studied in the last 20 years have shown various secondary metabolites and families of natural products that could be used to fight against antimicrobial resistance.Of particular interest, due to the events experienced by humanity in recent years, are antivirals.Many studies still need to be carried out to determine the structure-activity relationship of different compounds.However, it is assumed that natural products belonging to the same family will act similarly, but this still needs to be corroborated.The great wealth that Latin America presents regarding plant species variety can be used to benefit global health.

Figure 2 .
Figure 2. Structures of plant antimicrobial compounds found in medicinal plants from Latin America, from Table1.

Table 1 .
Antimicrobial mechanisms of plant compounds present in Latin American medicinal plants.

Table 1 .
. Antimicrobial mechanisms of plant compounds present in Latin American medicinal plants.
Figure 3. Structures of promising plant-derived compounds merit combating drug-resistant pathogenic microbes, from Table2.

Table 3 .
Mechanisms of action of families of antifungal drugs.

Table 4 .
Extracts of Latin American plants with activity against pathogenic fungi.

Table 5 .
Antiviral extracts derived from plants.