Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives
Abstract
:1. Introduction
2. Antimicrobial Activity of Medicinal Plant Extracts
3. Mechanisms of Action of Antimicrobial Agents
3.1. Bacterial Protein Biosynthesis
3.2. Inhibition of Nucleic Acid Synthesis
3.3. Cell-Wall Biosynthesis
3.4. Destruction of Bacterial Cell Wall
4. Mechanisms of Resistance to Antimicrobial Agents
4.1. Efflux Pump
4.2. Structural Modification of Porins
4.3. Enzymatic Inactivation
4.4. Destruction of Antibacterial Agent
4.5. Alteration of Target Sites
5. Antimicrobial Activity Mechanisms of Medicinal Plant-Derived Chemical Compounds
5.1. Alkaloids
5.2. Phenolic Compounds/Polyphenols
5.3. Sulfur-Containing Compounds
5.4. Coumarins
5.5. Terpenes
6. Interaction between Medicinal Plant Extracts and Conventional Antibiotics
7. Challenges Surrounding Medicinal Plant Antimicrobial Activity
7.1. Use of Antimicrobials from Medicinal Plant Extracts
- The use of medicinal plants has been associated with the adulteration of valuable compounds, poor cultivation and collection procedures, lack of standardization during preparation, poor storage conditions, ultimately affecting the process of development of new antimicrobials [191]. Factors such as the season of harvest, region of cultivation, plant parts used, and type of processing can affect the levels and mechanisms of various compounds in extracts. Therefore, the comparison of the different literature data for the plant extracts antimicrobial activity may be problematic due to the composition of plant extracts varying according to local climate and environmental conditions [82]. In particular, rainfall and humidity are versatile in different geographical locations, which could change the composition and production of the compounds when the same species medicinal plant is growing in different geographical locations. Moreover, global changing of climate is another challenge modulating the weather condition and therefore jeopardizing the compounds composition and production, even in the same geographical locations.
- It is difficult for scientists to map all the complex interactions that might be taken place between all the various compounds found in a medicinal plant. The detailed knowledge of the plant extracts composition is another inherent difficulty since these extracts contain many components and hence are difficult to interpret. The isolation of single compounds with the desired antimicrobial activity can be time- consuming and possibly requires a large amount of plant material. Rediscovery of the same compounds from different sources also presents problems. Thus, standardization, stability, and quality control are feasible, but not easy. However, the prospect to study a high quantity of unexplored compounds may contribute to the renovated attention on medicinal plants [192].
- Synergism among compounds in a complex mixture presents unique difficulties as the technology to study multiple compounds acting on potentially multiple biological targets has not yet been fully developed.
- Making arrangements for access to medicinal plant species can sometimes be difficult, especially in an international setting. Regulations concerning plant collation and plant export/import differ depending on where the research is being conducted [193].
7.2. Innovative Methods for the Preparation of Medicinal Plant Extracts Chemical Compounds
7.3. Determination of Antimicrobial Efficacy of Medicinal Plant Extracts
7.4. The Challenges of Development New Antimicrobials from Medicinal Plant Extracts
- The translation of in vitro studies to in vivo experiments and finally to human clinical trials has been the major challenge in the development of new antimicrobials. In vivo research should be carried out for a better understanding of the exact mechanisms of the medicinal plant chemical compounds and whether they can be considered an alternative or supplement to the existing strategies for the treatments of microbial diseases.
- Only medicinal plant extracts that inhibit the growth of microorganisms in low or moderated MIC values should deserve the utmost attention and additional research may be done [24].
- Extracts should also be tested for their MBC, because the bactericidal potential hinders the possibility of antimicrobial resistance.
- The utilization of unique traditional knowledge of medicinal plants medicine has great potential to generate biocompatible solutions and will hasten the discovery of new antimicrobials. This knowledge is important to design efficient and environmentally friendly technologies of fractionation and contribute to the effective exploitation of bioactive plant extracts.
- The method of extraction and in vitro testing should be standardized so that the search for new antimicrobial drugs from medicinal plants could be more systematic, and it will facilitate proper interpretation of results [34].
- Despite the increasing number of compounds isolated from antimicrobial medicinal plants, there are still only relatively few plant-derived drugs in clinical use. This may be because plant compounds often require complex combination effects between components to synergize the activity of the bioactive compound. A number of studies have shown that the overall activity of plant extracts can result from mixtures of compounds with synergistic, additive, and antagonistic activity [33,222,223,224,225]. Therefore, a major concern in the development of antimicrobials from medicinal plants is related to the possibility of synergism or antagonism effects due to the complexity in extracts composition [80,226]. Synergism within and between plant extracts have been extensively reviewed, providing compelling evidence that at least in some cases, the combined effect of plant mixtures is not simply the summation of their individual compounds [33,220,224,227,228,229]. However, it is likely that such combinations could produce antagonism, leading to the cancelation of the therapeutic effect [189]. The classification of combination effects within complex mixtures and the identification of contributing compounds remains a challenging task, particularly when most established tools have been designed to reduce complexity and identify single active compounds of natural products mixtures. Therefore, the use of bioassay-guided or synergy-guided fractionation to predict which compounds/mixtures are responsible for a specific activity is of extreme importance [225].
- Recent developments in metabolomics may play a key role in the identification and effective application of new occurring natural antimicrobials. Statistical modeling used to predict and correlate the metabolomic profile of extracts and their bioactivity has gained much attention [227]. However, there is a lack of consensus in the field about which reference models are best for defining combination effects, making the interpretation of studies challenging. Recent models using the specific mean equation [230] and the zero-interaction potency model [231] represent newly developed and robust reference models that may permit improved identification combination effects. There are also several emerging technologies, such as nanotechnology and bio-adhesive technology and materials, namely hydrogel formulations and active packaging materials which can enhance the effectiveness of plant antimicrobial compounds.
- The development of antimicrobials for oral therapy requires the application of methodologies that consider the effect of digestion on the bioactivity of the extracts [232]. However, even using sophisticated in vitro digestion models, it is still impossible to fully mimic the overall digestive parameters in vivo.
- Studies concerning the toxicity of the most promising medicinal plant extracts are major challenge for their use as antimicrobials [233,234]. Most extracts have not been evaluated by the U.S. Food and Drug Administration [235]. Therefore, the lack of official information regarding the actual toxicity of many extracts is concerning, since the adverse effects caused by the misuse of medicinal plants are characterized as a public health problem [236]. Reasons for plant extracts toxicity are improper identification/authentication and improper labeling on standardization. Thus, the extracts should be regulated through official controls and rigorous manufacturing standards.
- Another challenge in the development of antimicrobials from the medicinal plants is related to poor financial support for research and therefore lack of high- quality studies on the comprehension of structure-activity relationship with individual compounds [76].
7.5. Enhancement of the Antimicrobial Activity of Medicinal Plant Extracts
7.6. A Potential ‘ESCAPE’ from Antimicrobial Resistance of ‘ESKAPE’ Pathogens by Exploiting Medicinal Plants
8. Study Limitations
9. Future Perspectives
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Plant Sources | Class of Compound | Compound | Mechanisms | Susceptible Microorganism | References |
---|---|---|---|---|---|
Rauwolfia serpentine | Alkaloid | Reserpine | EP inhibitor | Staphylococcus sp., Streptococcus sp., Micrococcus sp., | [92] |
Piper nigrum | Piperine | EP inhibitor | MRSA, Staphylococcus aureus | [93] | |
Conessine | EP inhibitor | Pseudomonas aeruginosa | [94] | ||
Berberine | Protein and DNA synthesis inhibitor | Escherichia coli, Candida albicans | [95] | ||
Berberis vulgaris | Tomatidine | ATP synthetase inhibitor | Listeria, Bacillus Staphylococcus spp. | [96] | |
Phenolic compound/polyphenols | Rhamentin | EP inhibitor | Staphylococcus aureus | [97] | |
Camellia sinensis | Epigallocatechin gallate | Beta-ketoacyl-reductase | Escherichia coli | [98] | |
Chebulinic acid | DNA gyrase | Mycobactrium tuberculosis | [99] | ||
3-p-Trans-coumaroyl-2-hydroxyquinic acid | Cell membrane damage | Staphylococcus aureus | [100] | ||
Cedrus deodara | Apigenin | d-Alanine:d-alanine ligase | Helicobacter pylori, Escherichia coli | [101] | |
Allium sativum | Sulfur-containing compounds | Allicin | Protein and DNA synthesis inhibitor | Staphylococcus epidermidis, Pseudomonas aeruginosa, Streptococcus agalactiae | [102] |
Rubus ulmifolius | Ajoene | Sulphydryl-depe endent enzyme inhibitor | Cambylobacter jejuni, Streptococcus, Staphylococcus Escherichia coli | [88] | |
Sulforaphane | Destruction of bacterial membrane, Protein and DNA synthesis inhbitor, ATP synthase inhibitor | Escherichia coli | [103] | ||
Alyssin | Helicobacter pylori | [83] | |||
Raphanus sativus | Allyl isothiocyanate Benzyl isothiocyanate Phenethyl isothiocyanate | Bacillus subtilis,
Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Salmonella typhimurium, Enterobacter cloacae, Escherichia coli | [104] | ||
Ferulago campestris | Coumarin | Aegelinol | DNA gyrase inhibitor | Salmonella enterica serovar Typhi,
Enterobacter aerogenes, Enterobacter cloacae, Staphylococcus aureus | [105] |
Agasyllin | DNA gyrase inhibitor | Salmonella enterica serovar Typhi,
Enterobacter aerogenes, Enterobacter cloacae, Staphylococcus aureus, Helicobacter pylori | [105] | ||
Prangos hulusii | 4′-senecioiloxyosthol | DNA gyrase inhibitor | Bacillus subtilis | [106] | |
Osthole | DNA gyrase inhibitor | Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, MRSA | [106,107] | ||
Mesua ferrea | Bergamottin epoxide | EB inhibitor | MRSA | [108] | |
Thymus vulgaris | Terpene | Furnesol | Cell membrane disturbance | Staphylococcus aureus | [109] |
(4R)-carbone | Cell membrane disturbance | Cambylobacter jejuni, Enterococcus faecalis, Escherichia coli | [110] | ||
Thymol | Cell membrane (H+)-ATPase inhibition, Cell membrane disturbance, EP inhibitor | Candida albicans,
Candida glabrata, Candida crusei, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus niger, Aspergillus flavus, Fusarium oxysporum | [111] | ||
Carvacrol | Cell membrane disturbance, EP inhibitor | Escherichia coli,
Enterobacter aerogenes, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimarium. Aspergillus niger, Aspergillus fumigatus, Epadosporium spp., Rhizopus oryzae | [112] | ||
Cinnamaldehyde | Cell membrane disturbance | Helicobacter pylori | [113] |
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Vaou, N.; Stavropoulou, E.; Voidarou, C.; Tsigalou, C.; Bezirtzoglou, E. Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives. Microorganisms 2021, 9, 2041. https://doi.org/10.3390/microorganisms9102041
Vaou N, Stavropoulou E, Voidarou C, Tsigalou C, Bezirtzoglou E. Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives. Microorganisms. 2021; 9(10):2041. https://doi.org/10.3390/microorganisms9102041
Chicago/Turabian StyleVaou, Natalia, Elisavet Stavropoulou, Chrysa Voidarou, Christina Tsigalou, and Eugenia Bezirtzoglou. 2021. "Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives" Microorganisms 9, no. 10: 2041. https://doi.org/10.3390/microorganisms9102041