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Pharmaceutical Drug Regulatory Affairs Journal Research Article 27 min read

Antimicrobial Synergism within Plant Extract Combinations

Alqudah AA*
* Corresponding author
ISSN: 2642-6315  10.23880/pdraj-16000142  Received: August 14, 2023  Published: September 21, 2023
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Keywords
Synergy Antimicrobial Plant
Abstract

Ideas for research are drawn from the herbal medicine tradition of synergy. Using online databases, a study of the literature on plant synergy and antimicrobial research that was published in most recent years. In each plant sample, the efficacies of the various extract combinations varied, with some combinations of plant extracts exhibiting the greatest synergistic effects when combined according to proportionate extract yield. Since the beginning of time, herbal medicines and phytochemicals have been employed for their potent antibacterial action, and there is a growing trend toward the creation of plant-based natural products for the prevention and treatment of pathogenic infections. Utilizing antimicrobial agent-phytochemical combinations to neutralize the resistance mechanism and maintain the drug’s efficacy against resistant microorganisms is one method for successfully modifying resistance.

Introduction

Plants have been used for medicinal purposes long before prehistoric period and represent the most ancient form of medication. Ancient Unani manuscripts, Egyptian papyrus and Chinese writings described the use of herbs. Plant used for thousands of years in traditional medicine in many countries around the world [1, 2]. Most of the beneficial knowledge about their valuable effects was transferred over the centuries within human communities. Evidence from previous cultures like Indian, European, and Mediterranean have been using herbs for over 4000 years as medicine. Indigenous cultures such as Rome, Egypt, Iran, Africa, and America used herbs in their healing rituals [3, 4].

Nowadays, using of medicinal plant remains widespread, and plays a significant role of the world’s population herbal natural cures and supplements as the primary mode of healthcare. The World Health Organization stated that 80% of people in developing countries still rely on traditional medicine and utilize botanical supplements to treat disease [5, 6]. Plants consider as a valuable source of medicines because they provide a lot of bioactive molecules. Most of these molecules work as a chemical defence mechanism against infection and herbivores [7, 8, 9].

Historically, plants have provided a source of inspiration for novel drugs and have made large contributions to human health and well-being. Natural products have served as a major source of drugs for centuries and about 25—50% of current pharmaceuticals in use are derived from natural products [10, 11]. Medicinal plant extracts were reported for their anti-inflammatory [12, 13, 14], antibacterial [15, 16], antifungal [17, 18], and antiviral activities [19]. The interaction between antimicrobials in a combination can have three different outcomes, synergistic, additive, or antagonistic. Synergy occurs when a blend of two antimicrobial compounds has an antimicrobial activity that is greater than the sum of the individual components. An additive effect is obtained when the combination of antimicrobials has a combined effect equal to the sum of the individual compounds. Antagonism occurs when a blend of antimicrobial compounds has a combined effect less than when applied separately [20, 21]. This review aims to provide practical advice to investigators seeking to comprehensively evaluate the constituents and mechanisms responsible for the biological activity of botanical mixtures.

Antimicrobial Resistance

Some of the oldest life forms, bacteria are prokaryotic microorganisms that helped to build a world that is hospitable to animal life. Since the eighteenth century, there have been disagreements over whether environmental factors or microorganisms are to blame for the development of diseases [22, 23]. Antimicrobial resistance (AMR) is a pressing global health concern that poses a significant threat to our ability to treat infections effectively. It refers to the ability of microorganisms, such as bacteria, viruses, and parasites, to evolve and develop resistance to the drugs designed to kill or inhibit their growth. This phenomenon is primarily caused by the overuse and misuse of antimicrobial drugs in humans, animals, and agriculture [24, 25]. The consequences of AMR are far-reaching, as it can render once-effective antibiotics and other antimicrobial treatments ineffective, leading to prolonged illnesses, increased mortality rates, and higher healthcare costs [26]. To combat this growing problem, it is crucial to promote responsible use of antibiotics, develop new antimicrobial agents, enhance surveillance and monitoring systems, and educate healthcare professionals and the public about the appropriate use of these life-saving drugs [27]. Addressing antimicrobial resistance requires a coordinated global effort to preserve the effectiveness of existing treatments and safeguard future generations against the threat of untreatable infections [26]. Antibiotic resistance is becoming more and more widely recognized as a threat to public health, as is the rise in antibiotic resistance among bacteria that are significant human pathogens and the spread of resistance from the relatively closed environment of hospitals into open communities [28]. The development of multi-drug resistance or combinations of resistance, the emergence of new resistance mechanisms, and the ease with which genetic material encoding resistance may, in some circumstances, spread horizontally between different species of bacteria all contribute to a greater sense of helplessness against diseases that, when antibiotics were first invented, were believed to be under control [29, 30].

Bacteria have evolved and developed new bacterial resistance mechanisms in order to live due to a number of circumstances, including overuse of antibiotics in agricultural and healthcare [31]. Although thoroughly documented, it is still unclear how using a single antibiotic for just two weeks might cause bacteria in a human or animal body to become multidrug resistant (MDR) [32, 33, 34]. When bacteria resist one treatment, “it is almost as if they strategically anticipate the confrontation of other drugs” [33]. According to Smillie CS, et al. [34], horizontal genetic transfer of mobile characteristics is thought to be the cause of the startlingly large amount of transferable drug resistance between various species of bacteria. The Human Microbiome Project’s director, Blaser MJ, et al. [32], explains how a species’ microbiome is made up of the trillions of bacteria that have co-evolved to coexist with it. According to Blaser MJ, et al. [32], microbial symbionts make up 70–90% of human body cells and perform a variety of crucial metabolic and defensive tasks.

Plant Secondary Metabolites

Plant secondary metabolites, also known as phytochemicals, are organic compounds that are not directly involved in the essential functions of plant growth and development but play significant roles in plant defense mechanisms and interactions with the environment [35]. These compounds are produced by plants through various biochemical pathways and are often concentrated in specific plant tissues or organs, such as leaves, flowers, fruits, and roots [36, 37].

Plant secondary metabolites have diverse chemical structures and functions. They serve as defense mechanisms against herbivores, pests, and pathogens by deterring or repelling them, or by inhibiting their growth and development. Some secondary metabolites, such as alkaloids, phenolics, and terpenoids, have antimicrobial properties and can help plants combat infections [38, 39, 40]. The treatment of infections and health disorders with herbal medicines is usually involves active natural products mostly of low molecular weight of great structural diversity [41, 42]. More than 200,000 defined structures of plant secondary metabolites have been known. Some plants or their extracts with high concentrations of bioactive plant secondary metabolites such as saponins, tannins, essential oils, organosulphur compounds, flavonoids and many other metabolites have potential to treat many diseases [38]. Many scientific sources state that their role is not crucial for living cells in normal growth, development, and reproduction, but they act in defensive purposes to protect a plant from any possible harm in the ecological environment and other interspecies protection [43]. Many scientific sources state that while they serve defensive functions to protect the plant from potential harm in the ecological environment and other interspecies protection, their role is not essential for plant physiology in normal growth, development, and reproduction [40]. Consequently, they are typically produced in plants to meet specific needs, whereas primary metabolites typically serve the crucial biological functions in all species [44]. Secondary

metabolites produced by modified synthetic pathways from primary metabolite or share substrates of primary metabolite origin [45]. To adapt to their environment, plants have been genetically encoding a variety of helpful synthases for secondary metabolites. These substances, particularly essential oils, are utilized as medications, flavors, or sedatives in human life [46]. In most recent references, secondary metabolites extracted from plants are subdivided in three major classes: terpenoids, alkaloids and phenolics. They contain a huge number of organic compounds with intriguing pharmacological properties [38]. Here are a few examples of plant secondary metabolites and their association with specific diseases:

  • Flavonoids: Flavonoids are a class of secondary metabolites found abundantly in fruits, vegetables, and herbs. They possess antioxidant and anti-inflammatory properties [47, 48, 49], which make them beneficial in combating chronic diseases such as cardiovascular diseases [50], cancer [51, 52], and neurodegenerative disorders [53].
  • Alkaloids: Alkaloids are a diverse group of secondary metabolites that exhibit a wide range of pharmacological activities. For instance, alkaloids like vincristine and vinblastine from the Madagascar periwinkle (Catharanthus roseus) have been used as chemotherapy agents for the treatment of cancer [54]. Also, the anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of Alzheimer’s disease [55].
  • Terpenoids: Terpenoids, including essential oils, have been extensively studied for their antimicrobial [56], anti-inflammatory [57], and anticancer activities [58, 59]. Examples include the antimalarial drug artemisinin derived from Artemisia annua and the anticancer drug paclitaxel derived from Taxus brevifolia [60].
  • Phenolic compounds: Phenolic compounds, such as resveratrol found in grapes and berries, have shown potential in protecting against cardiovascular diseases and cancer [61]. They possess antioxidant properties and can help reduce oxidative stress and inflammation in the body [62, 63]. These compounds have been investigated for their potential role in preventing or treating various diseases, such as diabetes [64], cancer [65], cardiovascular diseases [66] and neurodegenerative disorders [67].
  • Glycosides: Plant glycosides have been investigated for their effects on various health conditions. For instance, cardiac glycosides derived from plants like Digitalis purpurea have been used to treat heart failure and certain arrhythmias [68, 69, 70].

It’s important to note that while plant secondary metabolites offer promising therapeutic potential, their efficacy and safety need to be further studied and validated through rigorous scientific research and clinical trials. Additionally, the appropriate dosage, administration, and potential interactions with medications should be carefully considered when utilizing plant secondary metabolites for disease prevention or treatment.

Development of Synergistic Effects of Plant Extracts

According to the presumption that a plant has one or a few chemicals that influence its medicinal effects, many scientists have focused for decades primarily on the search for the single active component in plants. But traditional systems of medicines like European phytotherapy and traditional Chinese Medicine assume that a synergy of all ingredients of the plants will result in the greatest medicinal efficacy [71]. Due to the lack of sufficient methods to standardize complex plant mixtures (as medications) and to explain the complicated mode of activities, this approach has long been impossible to research. The recent advancements in synergy research have opened highly interesting perspectives for a new generation of phytopharmaceuticals. The emergence and rapid shift in chemotherapy, involving the gradual change from the mono-substance therapy to a multidrug therapy with high efficiency [72, 73]. This is mostly due to the ineffectiveness, resistance issues, and potential side effects of synthetic mono-drugs, particularly when used to treat chronic conditions such as diabetes, cancer, inflammation, and atherosclerosis. The rationale behind employing multiple drug therapy for various disorders is the recognition that for each, more than one mechanism and gene is identified [74]. For instance, the pathway components that are altered in any individual tumor vary widely [75]. In addition, 12 partially overlapping processes that are genetically changed in the vast majority of pancreatic tumors have been identified by a global genomic investigation [76]. The complex multi-component character of medicinal herbs may serve as a rich resource for network-based multi-target drug discovery due to its potential therapeutic benefits by synergy. Herb extracts are complex combinations of main chemicals, concurrent drugs, and other substances [77]. Recently, Epigallocatechin gallate (EGCG), is able to increase the therapeutic effectiveness of temozolomide in patients with glioblastoma [78]. The EGCG can cross the blood–brain barrier to cause chemosensitization in a mouse glioma model. When the EGCG combined with temozolomide, the expression levels of glucose-regulated protein 78 in temozolomide-treated animals were reduced significantly, which plays a crucial role in pro-survival component of the endoplasmic reticulum stress response system (EGCG alone did not have any survival-enhancing effects) [79].

Synergistic Effect of Combinations of Herbal Extracts

Combining different plant extracts with various bioactive components has been shown to result in either synergistic or antagonistic effects in their bioactive effects. Synergistic effects can occur when the extracts of two or more plant species exhibit greater effects than the extracts of one plant species. Malongane F, et al. [80] found the common bioactive compounds mainly in green teas are flavan-3- ols (catechins), proanthocyanidins, flavonols and Black tea contains theaflavins and thearubigins and white tea contains L-theanine and gamma-aminobutyric acid (GABA), while herbal teas contain diverse polyphenols. All these phytochemicals in tea exhibit antimicrobial, anti-diabetic and anti-cancer activities that are perceived to be helpful in managing chronic diseases linked to lifestyle. Many of these phytochemicals are reported to be biologically active when combined. In a study achieved by Nuria I. Guardo, et al., 2017, fourteen essential oils (EOs) from selected live germplasm of medicinal plants have been tested for their antitrypanosomal and cytotoxic activity. And the study of the activity of these compounds in combination indicates the existence of synergistic effects depending on the concentration tested.

Antimicrobial Research and Plant Synergy

Research on the antimicrobial properties of plants and the potential synergistic effects of combining plant components has gained significant attention due to the increasing problem of antimicrobial resistance. Here are some aspects of recent studies on antimicrobial research and plant synergy:

  • Synergistic Combinations: Researchers have been investigating the combined effects of different plant extracts, essential oils, or phytochemicals to enhance their antimicrobial activity. Studies have explored combinations of plant extracts with known antimicrobial properties, such as tea tree oil, cinnamon oil, and oregano oil, and demonstrated enhanced effectiveness against various pathogens [81, 82, 83]. For example, a study published in the Journal of Applied Microbiology found that a combination of thyme and cinnamon essential oils showed synergistic activity against antibiotic-resistant bacteria [84].
  • Mechanisms of Action: Researchers are also investigating the mechanisms by which plant compounds exert their antimicrobial effects and whether combining different compounds can have additive or synergistic effects. Studies have explored the interactions between different phytochemicals and their impact on disrupting bacterial cell membranes, inhibiting enzyme activity, or interfering with microbial biofilms [85, 86].
  • Plant-Drug Combinations: Some studies have focused on the potential synergistic effects of combining plant extracts or phytochemicals with conventional antibiotics [87, 88]. The goal is to enhance the effectiveness of existing antimicrobial drugs and potentially reduce the required dosage, thus minimizing the development of drug resistance. For instance, a study published in the Journal of Ethnopharmacology investigated the synergistic effects of combining the antibiotic gentamicin with various plant extracts, showing enhanced antibacterial activity against multidrug-resistant strains [89].
  • Combination Therapy Against Biofilms: Biofilms are complex microbial communities that are highly resistant to antimicrobial agents. Researchers are exploring the use of plant extracts or phytochemical combinations to disrupt biofilms and enhance the efficacy of antimicrobial treatments. Studies have shown promising results in using plant-based formulations to target biofilms of various pathogens, including bacteria and fungi [90, 91].
  • Identification of Active Compounds: Advances in analytical techniques and screening methods have allowed for the identification of specific active compounds responsible for the antimicrobial effects of plants. Researchers are isolating and characterizing these compounds and investigating their interactions and potential synergistic effects when combined [92, 93].

It’s important to note that while these studies show promising results, further research is needed to fully understand the mechanisms and optimize the use of plant synergy in antimicrobial applications. Additionally, evaluating safety, dosage, and potential interactions with other medications is crucial for the development of effective and safe antimicrobial therapies.

Studies on Plant Synergistic Effect

Research on plant synergistic effects is a dynamic field with numerous studies exploring the combined effects of different plant components. Here are a few examples of studies conducted on plant synergistic effects:

  • Curcumin and Piperine: Curcumin, a bioactive compound found in turmeric, has shown various health benefits. However, its bioavailability is limited [94, 95]. Several studies have investigated the synergistic effect of combining curcumin with piperine, a compound derived from black pepper. Piperine has been found to enhance the absorption and bioavailability of curcumin, leading to improved therapeutic effects [96, 97, 98].
  • Green Tea and Citrus Flavonoids: Green tea is known for its antioxidant properties, while citrus fruits are rich in flavonoids [99]. A study published in the Journal of Nutrition demonstrated that combining green tea catechins with citrus flavonoids resulted in a synergistic effect, leading to enhanced antioxidant activity and protection against oxidative stress [80, 100].
  • Garlic and Onions: Garlic and onions are both rich in organosulfur compounds, which have antimicrobial and anticancer properties. Studies have indicated that the combination of garlic and onions may exhibit a synergistic effect in inhibiting the growth of cancer cells and enhancing the overall anticancer activity compared to using each ingredient individually [101].
  • Herbal Combinations in Traditional Medicine: Traditional medicine systems, such as Ayurveda and Traditional Chinese Medicine, often utilize combinations of multiple herbs to treat various ailments. Numerous studies have investigated the synergistic effects of herbal combinations and found that certain combinations exhibit enhanced therapeutic effects compared to individual herbs alone. For example, a study published in the Journal of Ethnopharmacology found that a combination of three herbs used in traditional Ayurvedic medicine showed stronger antidiabetic activity than when each herb was used separately [102, 103].
  • Essential Oils: Essential oils derived from different plant sources often consist of a complex mixture of compounds. Research has focused on studying the synergistic effects of these compounds. For instance, a study published in the Journal of Agricultural and Food Chemistry explored the synergistic antimicrobial effects of essential oil components from oregano, thyme, and clove against foodborne pathogens, demonstrating enhanced antimicrobial activity when the compounds were combined [104, 105].

These are several examples of the studies conducted on plant synergistic effects. Researchers continue to explore and unravel the interactions between plant components, aiming to optimize the therapeutic potential of plants and develop effective combination therapies for various applications.

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@article{alqudah2023,
  title   = {Antimicrobial Synergism within Plant Extract Combinations},
  author  = {Alqudah AA},
  journal = {Pharmaceutical Drug Regulatory Affairs Journal},
  year    = {2023},
  volume  = {6},
  number  = {1},
  doi     = {10.23880/pdraj-16000142}
}
Alqudah AA (2023). Antimicrobial Synergism within Plant Extract Combinations. Pharmaceutical Drug Regulatory Affairs Journal, 6(1). https://doi.org/10.23880/pdraj-16000142
TY  - JOUR
TI  - Antimicrobial Synergism within Plant Extract Combinations
AU  - Alqudah AA
JO  - Pharmaceutical Drug Regulatory Affairs Journal
PY  - 2023
VL  - 6
IS  - 1
DO  - 10.23880/pdraj-16000142
ER  -