Keywords

1 Introduction

Throughout history, humans have fought infections caused by viruses, bacteria, parasites, and fungi that cause colds, sexually transmitted diseases, digestive disorders, and many more. Today, these diseases are typically treated with synthetic drugs, including various antimicrobials, but before modern medications were available, humans turned to their environment to fight off infections. These remedies were often plant-based, including leaves, flowers, stems, barks, roots, as well as animal-based substances, such as honey, venom, and mucus. Civilizations from all regions of the world expended their environment to fight infections throughout history. There are records dating back thousands of years within various cultures and regions around the world describing the use of environment-based medicines. For example, China, a country well-known for its ancient remedies, has a medicinal system approximately twenty-three centuries old (Chen 2001). Chinese medicine has focused on the balance of Yin (passive) and Yang (active); however, when this balance is disrupted, it is believed to cause illness (Chen 2001). One of the earliest archives of medicine includes the use of orally and externally administered medicinal wine to ward off disease, dating as far back as 2500 BC during the Shang dynasty and Zhou dynasty (Xia 2013). In fact, it is believed that the first record of using medicinal plants is found in the text of The Divine Husbandman’s Classic of Materia Medica (ShenNong Ben Cao Jing), written in the late Eastern Han Dynasty (25–220 AD) (Jaiswal et al. 2016).

China isn’t the only country with a rich background in ancient remedies. India, for example, also has a long history of using natural remedies to treat illness, with the first record of using plants as medicine dating back to between 6000 and 4000 BCE (Pan et al. 2014). Ancient Indian remedies are based on approximately 25,000 plant formulations that have been used for almost 30 different types of human diseases (Sharma et al. 2007). Africa, having more than 5400 known species of plants used in traditional medicine, is another region of the world with a strong history of using environmental resources as medicine (Van Wyk 2015). For example, a well-known traditional plant dating back to prehistoric times, centella (C. asiatica), was utilized for wound healing, tuberculosis, lupus, inflammation, syphilis, diarrhea, and many more (van Wyk 2008). In 1500 BC, traditional medicinal practices were established in Mesoamerica and continued until the 1500s when the Spaniards arrived (Pena 1999). Two documents, the Badianus codex and the Sahagun codices, provide documentation of Aztec medicine before Columbian civilization (Guerra 1966). Native American medicinal practices frequently varied from tribe to tribe, but in many instances, healing required both rituals and botanical substances, ranging from over 200 different species of plants (Hershman and Campion 1985). However, medicinal practices quickly changed to treat infectious diseases like smallpox, influenza, measles, and other infections of European origin post-Columbus arrival. The Old English Herbarium, Bald’s Leechbook, and Lacnunga are some of the earliest recordings of medicine in Europe, dating back to the ninth century. Bald’s Leechbook, the most prominent of the three, was written around 950 AD. The chronicles examined remedies for various human diseases starting at the head and moving down toward the toes (Watkins et al. 2011). This series of records was composed of three books, the first two describing diseases of both external and internal complaints and the third providing a list of plant names and instructions (Watkins et al. 2011).

Within the last 100 years, modern medicine has implemented new ways of warding off infection through the use of medications, including antimicrobials (Yazdankhah et al. 2013). Near the start of the antibiotic era, the Surgeon General of the United States stated, “It is time to close the book on infectious diseases, and declare the war against pestilence won” (Spellberg and Taylor-Blake 2013). Assuming the fight against infection was over, the emphasis for discovery of new antimicrobial agents was tapered. However, the capacity for pathogens to evolve resistance to antimicrobials was soon apparent. In a 2011 national survey, 60% of infectious disease specialists had seen a microbial infection that was resistant to the first line of antibiotics within the last year, further proving the fight against microbial infections is far from over (Ventola 2015). As antimicrobial resistance continues to rise, the need for new methods of fighting infection is becoming abundantly clear. Interestingly, the answer to much-needed new forms of antimicrobial drugs might be found by looking at traditional medicine. In this review, we discuss the need for new antimicrobial agents and explore the potential of the natural remedies that have been used in different regions of the world throughout history.

2 Antimicrobial Resistance

Antimicrobial-resistant infections are an increasing problem within the medical field, and one of the major causes of mortality and morbidity (Martinez and Baquero 2014). As antimicrobial drugs continue to be overly prescribed and abused by clinicians, patients, and livestock farmers, bacteria have been pressured by their environment for survival (Ventola 2015; Michael et al. 2015; Shay and Freifeld 1999; Fiore et al. 2017; Grigoryan et al. 2007). The majority of antibiotics in use today are secondary metabolites derived from actinomycete bacteria (Mak et al. 2014) and target essential cell processes, such as protein synthesis, cell wall synthesis, and DNA synthesis (Mahajan and Balachandran 2012). However, bacteria can become resistant to these metabolites through various mechanisms. One way bacteria resist killing by antimicrobials is by pumping the drug out of the cell before it can act. Multidrug resistance efflux pumps are frequently found in clinical strains of bacteria (Alcalde-Rico et al. 2016; Sun et al. 2014). Efflux pumps provide bacteria the capability to extrude antimicrobials, as well as heavy metals, organic pollutants, quorum sensing signals, and other substances (Blanco et al. 2016). For example, many strains of Pseudomonas aeruginosa express an efflux pump, PA1874-1877, which can be overly expressed during infection and result in biofilm-specific resistance to antimicrobials (Alcalde-Rico et al. 2016; Zhang and Mah 2008).

Bacteria can also develop resistance to antimicrobials through mutations or the acquisition of new genes that confer resistance (Martinez and Baquero 2014). Mutations in the genes that code for targets, transporters, or proteins that pre-antibiotics use for either activation or entrance into the targeted bacteria can lead to resistance (Baquero et al. 2009). The acquisition of new resistance determinants can occur through horizontal gene transfer in multiple ways. Through conjugation, plasmids, integrons, transposons, genetic islands, and integrative conjugative elements can carry genetic information among bacteria. It has been hypothesized that these resistance genes originate from either environmental microbiota or commensal bacteria (Martinez and Baquero 2014; Sommer et al. 2009; Davies 1997). Frequently, the genetic information on these mobile genetic elements can insert themselves into the bacterial chromosomal DNA, which can be reversible or irreversible (Brown-Jaque et al. 2015). Without cell-cell contact, phages and genetic transfer agents can integrate genetic information into bacteria as well (Brown-Jaque et al. 2015).

Community-based resistance in the form of a biofilm promotes bacterial tolerance against antimicrobial agents. It is accepted that the majority of bacteria exist in a biofilm both in the environment and within the human body (Costerton et al. 1995). Biofilms are composed of a variety of microbes living in close proximity to each other and encased in a matrix that includes extracellular DNA (eDNA), exopolysaccharides, proteins, and various lipids (Donlan 2002). This matrix creates a barrier that can be exceptionally difficult for antimicrobial agents to penetrate and reach the bacteria within the biofilm. The bacteria in the biofilm generally live in an altered metabolic state in order to survive the low oxygen and nutrient-deplete environment (Penesyan et al. 2015). This slowed metabolism adversely impacts the capability of antimicrobials to enter the bacteria and work efficiently (Costerton et al. 1995). Persister cells, bacteria deep within the biofilm that have a slow or nongrowing phenotype, are highly resistant to antimicrobials (Conlon et al. 2015). Due to the mechanism of antibiotics, such as β-lactams that work by inhibiting growth factors, persister cells will oftentimes survive antimicrobial treatment, while the remaining bacterial population is killed off. This phenomenon can lead to recurring infections initiated by bacteria that have strategies for tolerating antimicrobials, producing further infections that are even more problematic (Cho et al. 2014). In conclusion, the vast variety and number of methods that bacteria can utilize to become resistant to antimicrobials further emphasize the need for new antimicrobial treatment agents.

3 Herbal Remedies

3.1 Africa

Africa, a continent of 54 countries, has one of the shortest life expectancies in the world at only 56 years (Kuate Defo 2014). One of the most virulent diseases in Africa is HIV/AIDS, with 5% of adults infected in Sub-Saharan Africa and 5.7% of adults in North Africa and the Middle East (Kilmarx 2009). Diarrheal diseases are another common infection seen in Africa, killing millions of children each year (Levine et al. 2013). Throughout the ages, people in Africa began utilizing various parts of plants and shrubs to help alleviate these diseases. Plants from the families of Guttiferae (Kuete et al. 2011), Apiaceae (El-Haci et al. 2014), Crassulaceae (Akinpelu 2000), Melastomataceae (Baba and Onanuga 2011), Bignoniaceae (Mbosso Teinkela et al. 2016), Fabaceae (Koffuor et al. 2014), Loranthaceae (Deeni and Sadiq 2002), and Balanophoraceae (Ohiri and Uzodinma 2000) were often used to treat diarrheal diseases and dysentery, and leaves from Sutherlandia frutescens (family: Fabaceae) were used to control HIV/AIDS (Koffuor et al. 2014). Many of these families also include plants that were used to treat various infections and signs of disease, such as tuberculosis (Baba and Onanuga 2011), colds (Sonibare et al. 2016; Selles et al. 2013), coughs (El-Haci et al. 2014; Akinpelu 2000; Baba and Onanuga 2011), headaches (Akinpelu 2000; Bisignano et al. 2000), and chest pain (Ohiri and Uzodinma 2000; Sonibare et al. 2016; Viljoen et al. 2003).

Interestingly, the majority of the plants that have been studied from Africa are either shrubs or flowering plants. Different elements of these plants have been tested for active molecules or phytochemicals to determine their antimicrobial mechanism(s) of action (MOA). Some of the most common phytochemicals found in this region include tannins (Baba and Onanuga 2011; Koffuor et al. 2014; Chah et al. 2000), saponins (Baba and Onanuga 2011; Koffuor et al. 2014; Chah et al. 2000), and alkaloids (Baba and Onanuga 2011; Chah et al. 2000; Lohombo-Ekomba et al. 2004). It is hypothesized that tannins inhibit biofilm formation, as they are bacteriostatic, and can damage bacterial membranes and negatively impact matrix production (Trentin et al. 2013). Saponins are molecules that become “soaplike” in water. Their antimicrobial MOA is thought to be disruption of the bacterial cell membrane, which leads to cell lysis (Arabski et al. 2012). The proposed MOAs of alkaloids, on the other hand, are to inhibit cell division and/or nucleic acid synthesis or to disturb the Z-ring at the site of division (Cushnie et al. 2014; Lutkenhaus and Addinall 1997). Table 1 details 29 different species of plants, with the majority native to central, western, or southern Africa.

Table 1 African remedies
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Along with plants, the mucus from Achatina fulica (giant African land snail) (Pitt et al. 2015), venom from Androctonus amoreuxi (African fat-tailed scorpion) (Almaaytah et al. 2012; Du et al. 2015), and propolis from bees (Suleman et al. 2015) have also been exploited in Africa for their antimicrobial properties.

3.2 Asia

For the context of this review, Asia includes Russia, China, India, the Middle East, Japan, and North and South Korea. Table 2 details 44 species of plants, royal jelly from honeybees (Fratini et al. 2016), and scorpion venom (Ahmed et al. 2012) that have been used medicinally as antimicrobials within this region of the world. Among plant-based medicines, herbs (Karuppiah and Rajaram 2012; Reiter et al. 2017; Ooi et al. 2006; Hong et al. 2014), mushrooms (Chowdhury et al. 2015), flowers (Hong et al. 2014; Ozusaglam et al. 2013; Yang et al. 2012; Sun et al. 2017), and fruits/berries (Shukla et al. 2016; Li et al. 2012; Paudel et al. 2014; Li et al. 2014) have been at the forefront. Bletilla ochracea (Chinese butterfly orchid), found throughout Vietnam and China, is particularly interesting due to the orchid’s history of being used to treat vampirism. It is fascinating that in parts of India and Thailand, Heterometrus xanthopus (giant forest scorpion) venom has been utilized as an antimicrobial agent. Meanwhile, venom from the African fat-tailed scorpion in North Africa exhibits similar antimicrobial properties. The majority of agents tested for their antimicrobial properties within this region have also served as treatments for diabetes (Ooi et al. 2006; Shukla et al. 2016; Paudel et al. 2014; Zeng et al. 2011; Liang et al. 2012) and digestive disorders (Ooi et al. 2006; Li et al. 2012; Paudel et al. 2014; Li et al. 2014; Zeng et al. 2011; Liang et al. 2012; Li et al. 2013a; Ma et al. 2015; Farzaei et al. 2014). Asian herbal remedies are depicted by their geographic location of use in the western, eastern, southern, or northern regions of Asia or as being exclusive to regions in India, Russia, or East Asian countries as seen in Fig. 1. Similar to the African traditional remedies, the most common phytochemicals found in Asia include tannins (Shukla et al. 2016; Paudel et al. 2014; Nemereshina et al. 2015), flavonoids (Hong et al. 2014; Chowdhury et al. 2015; Shukla et al. 2016; Zeng et al. 2011; Nemereshina et al. 2015; Su et al. 2012), and saponins (Koffuor et al. 2014; Shukla et al. 2016). Flavonoids can be found in vegetables, nuts, seeds, tea, wine, honey, stems, and flowers and have a long history of use for their antimicrobial effects. They have the ability to inhibit fungal spore germination and prevent infection and replication of viruses; however, the mechanism of their antibacterial properties is yet to be understood (Cushnie and Lamb 2005).

Table 2 Asian remedies
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Fig. 1
figure 1

Geographical distribution of ancient remedies by family classification focusing on Africa, Asia, Americas, and European and Mediterranean regions

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3.3 Americas

Within the Americas, ancient remedies can be further subdivided by either Canada/the USA, Mexico, Central America, or South America. Table 3 details 48 plant-based remedies and 3 animal-based remedies originating from these regions. Two of the animal-based remedies include venom from Hadrurus aztecus (Torres-Larios et al. 2000) and Vaejovis punctatus (Ramirez-Carreto et al. 2015), both scorpions found in Mexico. Intriguingly, Asia and northern Africa have also utilized venom from scorpions (Heterometrus xanthopus and Androctonus amoreuxi). H. xanthopus and H. aztecus both have the phytochemical hadrurin in common. Hadrurin is a known antimicrobial peptide that disrupts membrane organization in prokaryotic cells, leading to cell lysis, and it has been suggested that this peptide would be beneficial in treating Gram-negative bacterial infections (Sanchez-Vasquez et al. 2013). Although there are no other active molecules in common between the four venoms, there is overlap when looking at the microbial species that they have antimicrobial properties against. For example, A. amoreuxi and V. punctatus have an antifungal property active against C. albicans, and A. amoreuxi, H. aztecus, and V. punctatus exhibit antibacterial activity against E. coli, while H. xanthopus, H. aztecus, and V. punctatus are effective against P. aeruginosa (Sanchez-Vasquez et al. 2013).

Table 3 Americas
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Another animal-based remedy found within the Americas is mucus from Eptatretus stoutii (hagfish) (Subramanian et al. 2008). E. stoutii mucus has been shown to have antimicrobial properties against E. coli, P. aeruginosa, C. albicans, Staphylococcus epidermidis, and Salmonella enterica, but the active molecules responsible have yet to be determined. Remedies from the northern hemisphere also contain mucus from two fish, haddock and brook trout, suggesting the interesting possibility that fish mucus could have similar active compounds.

Within the Americas, there is a large overlap between remedies that have antimicrobial activity and those that were historically used for digestive disorders (Paudel et al. 2014; Davidson and Ortiz de Montellano 1983; Rodriguez-Garcia et al. 2015; Hernandez et al. 2007; Gutierrez-Lugo et al. 1996; Bolivar et al. 2011; Maldonado et al. 2005; Rivero-Cruz 2008; Hernandez-Hernandez et al. 2014; Cruz Paredes et al. 2013; Weckesser et al. 2007; Li et al. 2013b; Jimenez-Arellanes et al. 2013; Rivero-Cruz et al. 2011; Tan et al. 2014; Silva et al. 2016), rheumatism (Paudel et al. 2014; Weckesser et al. 2007; Jimenez-Arellanes et al. 2013; Tan et al. 2014; Fahed et al. 2017; Tan et al. 2015), and diabetes (Paudel et al. 2014; Gutierrez-Lugo et al. 1996; Rivero-Cruz 2008; Hernandez-Hernandez et al. 2014; Rivero-Cruz et al. 2011; Tan et al. 2014; Tan et al. 2015). Interestingly, there were also remedies commonly used for tuberculosis (Davidson and Ortiz de Montellano 1983; Rivero-Cruz et al. 2011; Tan et al. 2014). Tuberculosis was the leading cause of death in the early twentieth century; therefore, it is not surprising that herbal remedies were sought after to find a treatment for this disease (Abrams 2013). The most common phytochemicals utilized in the Americas include flavonoids (Gutierrez-Lugo et al. 1996; Bolivar et al. 2011; Cruz Paredes et al. 2013; Tan et al. 2014; Tan et al. 2015; Martinez Ruiz et al. 2012; Thiem and Goslinska 2004) and saponins (Davidson and Ortiz de Montellano 1983; Bolivar et al. 2011; Martinez Ruiz et al. 2012), which have already been discussed.

3.4 Northern Hemisphere

Throughout our review of the literature, there was a noticeable overlap of remedies between continents located in the northern hemisphere, including Asia, Europe, and North America. Table 4 details 22 plant-based remedies, as well as mucus from two fish, Salvelinus fontinalis (brook trout) found in freshwater and Melanogrammus aeglefinus (haddock) inhabiting saltwater. As a result of the cold climate in the northern latitudes, the majority of herbal remedies were derived from berries (Paudel et al. 2014; Taviano et al. 2011; Verma et al. 2014; Kylli et al. 2011), grass (Paudel et al. 2014), lichen (Paudel et al. 2014), or moss (Paudel et al. 2014), all of which can withstand the extreme temperatures in this region. The most common dual purpose for these herbal remedies overlaps between treatments for infection and urinary disorders, such as kidney and bladder stones, urinary tract infections, and incontinence (Paudel et al. 2014; Taviano et al. 2011; Kylli et al. 2011). The two most common phytochemicals from the northern hemisphere are tannins (Paudel et al. 2014; Taviano et al. 2011; Verma et al. 2014), similarly to those found in African and Asian remedies, and proanthocyanidins (Paudel et al. 2014; Kylli et al. 2011), condensed tannins that, as mentioned earlier, can impact biofilm formation.

Table 4 Northern Hemisphere (Europe, Asia, North America)
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3.5 Other

Other regions include the European, Mediterranean, and Arctic regions. Table 5 includes 21 plant-based remedies from the European and Mediterranean regions, along with 2 animal-based remedies. One animal-based remedy is coelomic fluid from Echinus esculentus, the European edible sea urchin, that exhibits antimicrobial effects on a variety of microorganisms including E. coli, S. aureus, P. aeruginosa, and others (Solstad et al. 2016). Another animal-based remedy is mucus from Helix aspersa, the brown garden snail. This mucus has been used for skin regeneration and exhibited an antimicrobial effect against S. aureus and P. aeruginosa (Pitt et al. 2015). Allantoin, a compound found in the mucus, is valuable for healing as it promotes keratolysis and impacts cell proliferation (Tsoutsos et al. 2009). The mucus from the giant African land snail also exhibits similar antimicrobial properties (Pitt et al. 2015). The majority of plant-based remedies were derived from the leaves (Hernandez-Hernandez et al. 2014; Fahed et al. 2017; Pavlovic et al. 2017; Quave et al. 2015; Antunes Viegas et al. 2014; Bouyahyaoui et al. 2016) or the bark/twigs (Fahed et al. 2017; Taviano et al. 2011; Apetrei et al. 2011). The most common phytochemicals within this region are flavonoids (Taviano et al. 2011; Pavlovic et al. 2017; Antunes Viegas et al. 2014; Apetrei et al. 2011; Tadic et al. 2008), also one of Asia’s top active molecules. Only three antimicrobial remedies, as seen in Table 6, were found in the Arctic regions of the world, all of which were classified as a lichen (Paudel et al. 2014), but there have been no published studies analyzing the phytochemicals of these plants. In fact, there is lack of reports on the history of lichens being used for any form of ancient remedy.

Table 5 European and Mediterranean remedies
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Table 6 Arctic
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4 Conclusions

Various segments of plants and animal products have been used by humans for thousands of years to ward off disease and infection. In some instances, concentrated oils and topical application of various plant and animal agents have shown enhanced antimicrobial effects in comparison to the current marketed antimicrobials and wound dressings. Although phytochemicals within these agents need to be further identified and understood, these active molecules could potentially increase our armamentarium of agents to combat antimicrobial-resistant infections. As these compounds continue to be studied, they could be of therapeutic value, and as modern medicine continues to lose the battle against antimicrobial resistance, the answer to fight back could be discovered by looking into the past. A notable example of this was a recent study that sought to reconstruct a recipe that was used in medieval times by Anglo-Saxons to treat eye infections. The recipe from Bald’s Leechbook was translated, made in the laboratory using medieval techniques, and then tested in mice with methicillin-resistant S. aureus (MRSA) infections (Harrison et al. 2015). The investigators demonstrated that the medieval recipe was more efficacious at treating this modern-day, drug-resistant infection than the current last line therapy, vancomycin. Thus, with the combination of ancient antimicrobial agents and a modern understanding of medicine, new remedies could impact our battle against persistent microbial infections.