Efficacy and Mechanism of Traditional Medicinal Plants and Bioactive Compounds against Clinically Important Pathogens

Traditional medicinal plants have been cultivated to treat various human illnesses and avert numerous infectious diseases. They display an extensive range of beneficial pharmacological and health effects for humans. These plants generally synthesize a diverse range of bioactive compounds which have been established to be potent antimicrobial agents against a wide range of pathogenic organisms. Various research studies have demonstrated the antimicrobial activity of traditional plants scientifically or experimentally measured with reports on pathogenic microorganisms resistant to antimicrobials. The antimicrobial activity of medicinal plants or their bioactive compounds arising from several functional activities may be capable of inhibiting virulence factors as well as targeting microbial cells. Some bioactive compounds derived from traditional plants manifest the ability to reverse antibiotic resistance and improve synergetic action with current antibiotic agents. Therefore, the advancement of bioactive-based pharmacological agents can be an auspicious method for treating antibiotic-resistant infections. This review considers the functional and molecular roles of medicinal plants and their bioactive compounds, focusing typically on their antimicrobial activities against clinically important pathogens.


Introduction
The incidence of microbial infectious diseases and their hitches consistently elevates, mostly due to microbial drug resistance to presently offered antimicrobial agents [1]. These multidrug-resistant microbes cause various infections globally and are connected with greater levels of morbidity and mortality [2]. These augmentations of antibiotic resistance and higher recurrence rates of such common infections have a great impact on our society [3][4][5]. Several investigations associated with antimicrobial resistance predict that the mortality toll owing to antimicrobial resistance may exceed 10 million by 2050, theoretically leading to greater mortality in the context of other infectious diseases and malignancies [6]. It is well known that infections are generally difficult to treat due to the development of biofilm in the host, which aids the proliferation of microbes as well as the aggressiveness of the infections [7]. Studies have also well-established that the physical structures of biofilm establishing organisms confer natural resistance to hostile environments, including antimicrobial agents [8]. Therefore, it is an urgent requirement to generate novel antimicrobial drugs which can inhibit the development of, or abolish the complete biofilms, and hence increase the vulnerability of microbes to antimicrobials. The requisite for new antimicrobials which could meritoriously fight against antimicrobial resistant clinical pathogens is extremely augmented.
Plant-derived antimicrobials have been established to be one of the most auspicious sources considered as safe due to their natural origin when compared with synthetic compounds [9,10]. There

Traditional Medicinal Plants
The species of the plant kingdom are estimated to number about 500,000 and only a minor portion of them have been investigated for antimicrobial activity [9,14]. Traditional medicinal plants can be cultivated by humans over centuries without existing systematic standards and analysis due to their safety and efficacy. Hence, bioactive compounds derived from these medicinal plants apparently have more potential to succeed in toxicology screening when compared with the de novo synthesis of chemicals. The cumulative attention on traditional ethnomedicine may lead to the revealing of innovative therapeutic agents since traditional medicinal plant contains potential antimicrobial components that are beneficial for the development of pharmaceutical agents for the therapy of ailments. Nowadays, studies are progressively turning their consideration to traditional medicine and advancing better drugs to treat diabetes, cancer, and microbial infections [15,16]. A large number of studies have been piloted using medicinal plant extracts and their active principles on bacteria, fungi, algae, and viruses in different localities of the world [9,10]. Various families of traditional medicinal plants have been scientifically tested for their antimicrobial activities and are presented in Table 1. The extracts of plant organs, namely the root, stem, rhizome, bulb, leaf, bark, flower, fruit, and seed, may encompass distinctive phytochemicals with antimicrobial activities [17]. It is well-known that sole plant species of traditional medicine are habitually used to heal a great number of infections or diseases [18]. The plant extracts with an antiquity of folk use should be confirmed using contemporary methods for activities against human pathogens with the intention of identifying potential novel therapeutic drugs. * MIC (minimum inhibitory concentration) is the lowest drug concentration at which a given antimicrobial extract inhibits the visible growth of a tested organism. MIC absolute value: the given absolute value of drug concentration inhibits the growth of all tested organisms/ MIC ranges: the given range of drug concentrations (minimum to maximum) inhibit the growth of the individual to all tested organisms.

Phytocomponent Fractions and Antimicrobial Methods
Fresh or dried plant extracts were prepared using aqueous and different organic solvents in traditional extraction techniques (maceration, percolation, Soxhlet extraction). During the extraction method, the solvents penetrate into the plant material and dissolve active compounds with a related polarity [62]. At the completion of the technique, solvents have been vaporized, resulting in the formation of a concentrated mixture that yields the active compounds [63]. A successful extraction is mainly reliant on the nature of the solvent utilized during the extraction. The most regularly established extracts are aqueous extract followed by organic solvents, which include using methanol, ethanol, hexane, isopropanol, ethyl acetate, benzene, acetone, chloroform, and dichloromethane [64].
Two popular types of antibacterial susceptibility test, namely diffusion and dilution methods, are generally performed to determine the antibacterial efficacy of the plant materials. The method of diffusion is a screening test to classify bacteria that aid susceptibility or resistance to the tested plant material based on the size or diameter of the inhibition zone [62]. On the other hand, the activity of plant materials is determined as minimum inhibitory concentration (MIC) in the dilution method. In the MIC method, the lowest concentration is capable of inhibiting bacterial growth. Redox indicators and turbidity are most often measured for the analysis of results in broth dilution methods. The turbidity can be calculated colorimetrically while changing the indicator color represents the inhibition of bacterial growth [62]. The screening of traditional plant extracts has been of great attention to researchers investigating novel bioactive compounds effective in the treatment of microbial infections. Plant extracts exhibit: (a) direct antimicrobial activity presenting effects on metabolism and development of microbes and (b) indirect activity as antibiotic resistance adapting substances which, joint with antibiotics, upsurge their efficiency. Numerous studies have considered the antimicrobial screening of traditional plant extracts. The studies of medicinal plants from diverse topographical areas include: Armenia [65], Iran [66], Mexico [67], Saudi Arabia [68], Libya [26], Ethiopia [64], India [63], Poland [69], Cameroon [70], Nigeria [71], and other Middle Eastern countries [72]. Based on the available information, the traditional plant extracts showed antimicrobial activity against a huge number of pathogenic bacteria, fungi, viruses, algae, protozoan, and Trypanosoma [26,63,64,66].

Mechanism of Actions of Antibacterial Bioactive Compounds
As proven by in vitro experiments, medicinal plants produce a boundless quantity of secondary metabolites that have great antimicrobial activity [9,10,18]. These plant-produced low molecular weight antibiotics are classified according to two types, namely phytoanticipins, which are involved in microbial inhibitory actions, and phytoalexins, which are generally anti-oxidative and synthesized de novo by plants in response to microbial infection [16,74]. Plant antimicrobial secondary metabolites are generally categorized into three broad classes, namely phenolic compounds, terpenes, and alkaloids. Numerous studies have shown that the antimicrobial activity of the plant extracts and their active compounds have the following potential: to promote cell wall disruption and lysis, induce reactive oxygen species production, inhibit biofilm formation, inhibit cell wall construction, inhibit microbial DNA replication, inhibit energy synthesis, and inhibit bacterial toxins to the host [75,85,[105][106][107][108][109]. In addition, these compounds may prevent antibacterial resistance as well as synergetics to antibiotics, which can ultimately kill pathogenic organisms (Figure 1).

Mechanism of Actions of Antibacterial Bioactive Compounds
As proven by in vitro experiments, medicinal plants produce a boundless quantity of secondary metabolites that have great antimicrobial activity [9,10,18]. These plant-produced low molecular weight antibiotics are classified according to two types, namely phytoanticipins, which are involved in microbial inhibitory actions, and phytoalexins, which are generally anti-oxidative and synthesized de novo by plants in response to microbial infection [16,74]. Plant antimicrobial secondary metabolites are generally categorized into three broad classes, namely phenolic compounds, terpenes, and alkaloids. Numerous studies have shown that the antimicrobial activity of the plant extracts and their active compounds have the following potential: to promote cell wall disruption and lysis, induce reactive oxygen species production, inhibit biofilm formation, inhibit cell wall construction, inhibit microbial DNA replication, inhibit energy synthesis, and inhibit bacterial toxins to the host [75,85,[105][106][107][108][109]. In addition, these compounds may prevent antibacterial resistance as well as synergetics to antibiotics, which can ultimately kill pathogenic organisms (Figure 1).

Promote Cell Wall Disruption and Lysis
Phenolic compounds are a family of aromatic rings consisting of a hydroxyl functional group (-OH) which is alleged to absolute toxicity to microorganisms, although increased reactions of hydroxylation result in microbial cell lysis [110]. Quinones also have aromatic rings with two ketone molecules, which enables the production of an irreversible complex with nucleophilic amino acids, resulting in greater antimicrobial properties. These potential aromatic compounds are usually targeted to microbial cell surface adhesins, membrane-bound polypeptides, enzymes, and eventually lysis of the microbes [111]. Flavonoids are hydroxylated phenolic substances which are also able to complex with bacterial cell walls and disrupt microbial membranes [75,105]. Highly active flavonoids, quercetin (1), rutin (2), naringenin (3), sophoraflavanone (4), tiliroside (5) and 2, 4, 6trihydroxy-30-methyl chalcone (6) (Figure 2) decreased lipid bilayer thickness and fluidity levels and increased membrane permeability, supporting the leaking of intracellular protein and ions in S. aureus and S. mutans [112,113]. These compounds contribute to the synergistic effect with ampicillin and tetracycline [114]. The other active flavonoids, acacetin (7), apigenin (8), morin (9), and rhamnetin

Promote Cell Wall Disruption and Lysis
Phenolic compounds are a family of aromatic rings consisting of a hydroxyl functional group (-OH) which is alleged to absolute toxicity to microorganisms, although increased reactions of hydroxylation result in microbial cell lysis [110]. Quinones also have aromatic rings with two ketone molecules, which enables the production of an irreversible complex with nucleophilic amino acids, resulting in greater antimicrobial properties. These potential aromatic compounds are usually targeted to microbial cell surface adhesins, membrane-bound polypeptides, enzymes, and eventually lysis of the microbes [111]. Flavonoids are hydroxylated phenolic substances which are also able to complex with bacterial cell walls and disrupt microbial membranes [75,105]. Highly active flavonoids, quercetin (1), rutin (2), naringenin (3), sophoraflavanone (4), tiliroside (5) and 2, 4, 6-trihydroxy-30-methyl chalcone (6) (Figure 2) decreased lipid bilayer thickness and fluidity levels and increased membrane permeability, supporting the leaking of intracellular protein and ions in S. aureus and S. mutans [112,113]. These compounds contribute to the synergistic effect with ampicillin and tetracycline [114]. The other active flavonoids, acacetin (7), apigenin (8), morin (9), and rhamnetin (10) (Figure 2) cause weakening of the bacterial cell wall by disarrangement and disorientation of the lipid bilayer and ultimately persuade vesicle leakage [115][116][117]. The synthetic flavonoid lipophilic 3-arylidene (11) was found to be very active against S. aureus, S. epidermidis, and E. faecalis due to a bacterial cell clump that influences the integrity of the cell wall as a result of biofilm disruption [118]. Tannins are classes of another polymeric phenolic substance, characterized as astringency, which is capable to deactivate microbial adhesins, enzymes, and membrane transporter systems [105,119]. Coumarins (12) are benzo-α-pyrones known to stimulate macrophages, which could have an adverse effect on infections [7,120]. Terpenes are organic compounds containing isoprene subunits, which involve microbial membrane disruption [121,122]. Thymol (13), eugenol (14), Cinnamaldehyde (15), carvone (16), and carvacrol (17) (Figure 2) disintegrate the external membrane of various Gram-negative bacteria, releasing LPS and increasing the permeability [123][124][125].  [115][116][117]. The synthetic flavonoid lipophilic 3arylidene (11) was found to be very active against S. aureus, S. epidermidis, and E. faecalis due to a bacterial cell clump that influences the integrity of the cell wall as a result of biofilm disruption [118].

Mechanism of Resistance to Antibacterial Agents
Pathogenic bacteria generally receive the resistance to various antibiotics through diverse mechanisms. Such mechanisms include: (a) bacteria can share the resistance genes through transformation, transduction, and conjugation; (b) bacteria produce various enzymes to deactivate the antibiotics through the process of phosphorylation, adenylation, or acetylation; (c) damage or alteration of the drug compound; (c) prevent the interaction of the drug with the target; (d) efflux of the antibiotic from the cell [168][169][170]. Emodin (1, 2, 8-trihydroxy-6-methylanthraquinone) (64) is an anthraquinone derivative which prevents the transformation of resistance genes in S. aureus [171]. Baicalein is a potent inhibitor of the expression of the SOS genes, RecA, LexA, and SACOL1400 that prevent rifampin-resistant mutation in S. aureus [172]. Phenolic compounds such as Carnosic (65) and rosmarinic acids (66) inactivate cmeB, cmeF, and cmeR genes in Campylobacter jejuni [173].

Antimicrobial Action with Generation of Reactive Oxygen Species
Reactive oxygen species (ROS) can be formed by the partial reduction of molecular oxygen that targets the exertion of antimicrobial activity, which aids host defense against various disease-causing pathogens. The suggested method of antimicrobial activity of catechins (34) involves augmentation of the production of oxidative stress (ROS and RNS), which can alter membrane permeability and cause as cell wall damage [174]. In addition, catechins damage liposomes as they contain a high amount of negatively charged lipids and are susceptible to damage [175]. An earlier study indicated that catechins support the leaking of potassium and disturbs the membrane transport system in a methicillin-resistant S. aureus strain [85]. This team has further demonstrated that acylated 3-O-octanoyl-epicatechin (21) is a lipophilic compound that produces more outcomes in antibacterial activity.

Conclusions
Since time immemorial, traditional medicinal plants have been cultivated by diverse populations to treat a great number of infectious diseases. Various investigations on the pharmacognostics and kinetics of medicinal plants have shown that crude extracts and plant-derived bioactive compounds may enhance the effects of traditional antimicrobials, which may be cost-effective, have fewer side effects, and improve the quality of treatment. Numerous studies have shown that the antimicrobial activity of plant extracts and their active compounds have the following potential: promote cell wall disruption and lysis, induce reactive oxygen species production, inhibit biofilm formation, inhibit cell wall construction, inhibit microbial DNA replication, inhibit energy synthesis, and inhibit bacterial toxins to the host. In addition, these compounds may prevent antibacterial resistance as well as synergetics to antibiotics, which can ultimately kill pathogenic organisms. Based on these comprehensive antimicrobial mechanisms, the cultivation of traditional plant extracts and bioactive compounds offers a promising treatment for disease-causing infectious microbial pathogens. Hence, this mechanism constitutes an encouraging ally in the development of pharmacological agents required to combat the growing number of microbial strains that have become resistant to extant antibiotics in clinical practice.