Planetary Health and Traditional Medicine: A Potential Synergistic Approach to Tackle Antimicrobial Resistance

Abstract

Antimicrobials are compounds that impede the activities of bacteria, viruses, parasites, or fungi. Continuous antimicrobial overuse, misuse, and improper use for human, animal, and agricultural purposes are raising concerns about antibiotic residue pollution in the environment, and antibiotic resistance genes (ARGs). Because antimicrobial-resistant diseases are linked to human–-microbial ecosystems, environmental pollution from antibiotic residue and ARGs alters the makeup and diversity of human gut microbiota, putting resistance under selection pressure. This perspective proposes that antibiotic-induced microbiome depletion is linked to environmental quality and has repercussions for human health via the gut microbiome’s sensitive ecosystem. This has stimulated new global efforts and multidisciplinary, integrative approaches to addressing Antimicrobial Resistance (AMR) awareness in communities. Several academic papers published in recent years have shown that medicinal plant extracts are effective against diseases on WHO’s pathogen priority lists (PPL), such as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Traditional medicine, with its knowledge of medicinal plants, promises to be a valuable source of next-generation powerful antimicrobials. Examples include the recent discovery of Artemisinin, a highly active antimalarial drug derived from Artemisia annua, and the discovery of Taxol, an active chemotherapeutic drug derived from the bark of the Pacific yew, Taxus brevifolia. The connections between small and large ecosystems’ vitality, biodiversity protection, and human health have been acknowledged by Planetary Health principles. To address these intertwined concerns, a Planetary Health and Traditional Medicine approach can be adopted, and antimicrobial resistance can be addressed by expanding the screening of medicinal plants for bioactive compounds.

1. Introduction

Antimicrobial Resistance (AMR) is recognized as one of the top ten growing public health threats, currently estimated to account for more than 700,000 deaths per annum worldwide [1]. If adequate care is not taken, this figure may rise substantially to 10 million by 2050, thus, leading our planet to the post-antibiotic era. Antibiotics are overused in many countries around the world for the prevention and treatment of bacterial infections in humans and animals, as well as prophylaxis, metaphylaxis, and growth-promoting factors in livestock farming [1]. The disposal into natural environments of untreated human and livestock waste containing Antimicrobial Resistant Genes (ARGs) and antibiotics residue often usually results in the emergence of resistant bacteria [1,2]. Frontline antibiotics are overly used, including fluoroquinolones, third- and fourth-generation cephalosporins, and carbapenems, thereby contributing to increased multidrug resistance [3]. Antibiotic resistance is not restricted to human medicine: about 66% of antimicrobials are used in animal production [4], and resistance is prevalent there as well, even on organic farms that limit antimicrobial use [5]. On the other hand, the increased public threat of protozoal disease has been linked with environmental changes and ecological modifications arising from anthropogenic activities. These can result in the spread of anti-protozoal drug resistance [6] such as chloroquine for malaria, metronidazole for anaerobic parasites, sulphonamides for Toxoplasma gondii, and diloxanide for an enteric protozoan. In future, infection is likely to proliferate due to the lack of effective vaccines and safe and affordable drugs for the prevention and treatment of these diseases [7]. It is critical for endemic countries to protect the efficacy of protozoal treatments (malaria, leishmania, and trypanosomiasis) [8] and to develop innovative strategies focused on new antiprotozoal drugs [7]. Long-term strategies, however, are required to achieve the ultimate goal of preventing the emergence and spread of parasites resistant to currently available drugs. The magnitude and ramifications of rising antimicrobial drug resistance, emerging cross-resistance, along with a scarcity of novel medications, call for efforts that contribute to a broader understanding while considering alternative solutions. The alternative solution requires a multi-system approach, such as traditional medical system synergised with the western medical system. For example, Artemisinin—a highly powerful antimalaria drug derived from Artemisia annua—has recorded a high success rate in the treatment of chronic malarial diseases. As part of the efforts to increase the efficacy of this drug for resistance clearance, it has been combined with other compounds such as lumefantrine. However, irrational usage and over-use of Artemisinin-based combination therapies (ACTs) combined with an increased level of parasite adaptability at the genetic level has resulted in parasite resistance to Artemisinin and its partner drugs. As a result of this, a multidisciplinary, integrated, and intersectoral approach is required to avoid silo thinking when addressing the threat of AMR, and to achieve long-term global sustainability.

2. Factors Promoting the Spread of AMR

To effectively address the threat posed by AMR, it is necessary to first comprehend the factors that have led to its establishment. The rapid replication cycle of resistant organisms such as Staphylococcus aureus can contribute to the spread of AMR by creating approximately 1 million progenies in less than 12 h, resulting in de novo mutation [9]. Naturally occurring resistance can also play a crucial role, as Yukon discovered among bacteria with resistance mutations in permafrost samples from 30,000 years before the discovery of penicillin [10], and in samples from a cave ecosystem that had been isolated for more than 4 million years [11]. The use of antibiotics as growth promoters is an important factor contributing to resistance; the history of the growth promotion effect of antibiotics dates to the 1940s when livestock fed with dried mycelia of Streptomyces aureofaciens showed improved growth due to the constituent chlortetracycline residues therein. Since then, antibiotics have been widely used in farm animal and poultry feeds to promote growth [12]. For example, it has been revealed that about 80% of antibiotics in the US are used in food-producing animals [13,14] and the US Food and Drug Administration (FDA) estimates that 74% of these antibiotics are administered to promote animal growth, rather than to treat or prevent infection [15]. Moreover, 62% of the antibiotics used in animals are medically important compounds for treating human diseases, with the remaining 38% having the potential to influence human health in the US [15]. Several steps have been taken to control antibiotics usage in livestock feeds, including regulations and banning antibiotics such as vancomycin that are especially important in human medicine [16]. For instance, European countries such as Sweden and Denmark have placed a ban on the use of vancomycin, while avoparcin was never approved for use in livestock feed in the US [16]. Although the direct impact of such practices on human health has proven difficult to evaluate, several studies have shown the transmission of resistant bacteria via animal-to-human contact and human consumption of animal products [17,18].

The improper and unregulated disposal into the environment of pharmaceutical, municipal, and clinical waste containing AMR determinants such as ARGs creates a complex interface for microbial interaction, while stresses on these microbes can increase their rate of resistance to antibiotics [19]. Consequently, dissemination of antibiotics residue from livestock, including poultry and other food-producing animals such as fish, usually involves dispersal into the environment through antimicrobial excretion in urine and feaces, and discharge of untreated excretory products into soil or water bodies, where humans can become infected through contact with a polluted environment [20,21].

The role of environmental compartments (soil, water, and air) in the spread of AMR has been elucidated by many researchers [22,23,24]. Soil, as one of these important compartments, can harbor resistant bacteria for a very long period while simultaneously acting as a natural reservoir for ARGs—these genes, which outnumber clinically resistant ones, are usually transmitted to humans and can spread independently of anthropogenic activities [19]. Furthermore, anthropogenic activities including mining, farming, and land-use change, expose soils to heavy metals contamination. These heavy metals have been shown to persist in the environment for long periods and to function as selection agents for antibiotic-resistant microbes in the soil, resulting in a rise in bacterial population resistance [19,22].

3. ESKAPE Pathogens

Pathogens’ intrinsic physiological mechanisms provide the evolutionary underpinning of resistance to manmade antibiotics [25]. Endogenous resistance develops through random chromosomal point mutations, with subtherapeutic antibiotic concentrations increasing mutability and selection for resistant strains. Exogenous resistance develops via horizontal gene transfer—mobilized via conjugative plasmids, transposons, and insertion sequences—and the recombination of foreign DNA into the chromosome [26]. In a bid to address rising instances of mutations and resistance, the World Health Organization released the global priority pathogen list (PPL) in 2016, to guide researchers in the research and development (R&D) of novel and active antibiotics for effective treatment of multi-drug resistant (MDR) infections caused by emerging and reemerging superbugs. Prominent on this list are the ESKAPE pathogens, which have been reported to be responsible for the highest mortality from nosocomial infections, concomitant with increased healthcare costs from hospitalization [27]. The acronym ESKAPE encompasses the six most highly virulent and multi-drug resistant pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) responsible for global health threats caused by misuse and abuse of antimicrobials [27]. Antibiotics are used singly or in combination to treat infections in general antimicrobial therapy, but the overall number of medications effective against ESKAPE is diminishing with each passing year, indicating a future in which the efficacy of antibiotics is much reduced [28]. According to analysis of the antibiotic lists recommended by the Clinical & Laboratory Standards Institute (CLSI), numerous medications formerly indicated against ESKAPE have been removed, while only a few drugs/antibiotics such as dalbavancin, telavancin, and aztreonam have been added since 2010 [29]. Furthermore, resistance to several of the newly added antibiotics has been documented, prompting the development of novel treatment approaches, particularly for ESKAPE-related bacteria [29]. Improved understanding of these bacteria’s virulence, resistance, transmission, and pathogenicity could lead to novel antimicrobial development strategies. Focusing attention on the most tenacious and pathogenic microbes will assist in narrowing the scope of the AMR problem and allow for more efficient critical evaluation of new antimicrobial drugs [25]. While the tension of investing in research and development of new antimicrobials is well recognized and appreciated, it is important to note that if regulatory policies are not put in place to tackle environmental reservoirs of AMR such as biofilms, the threat of AMR will continue to jeopardize the effort of pharmaceutical industries in screening natural bioactive products for novel drug discovery [30]. Unfortunately, it is worthy of note that in the last couple of years several research-based big pharmaceutical companies have halted the research and development of antibiotics, while others have left the field of antibiotics R&D [31]. Even though several commitments have been made by the private sector through the AMR Industry Alliance, tangible action is still very limited [31,32]. However, through their efforts in producing active medicines such as fexinidazole (an active drug against sleeping sickness), several malaria medicines, and pretomanid (an antibiotic drug for the treatment of multi-drug resistant tuberculosis), product development partnerships including the Drugs for Neglected Diseases initiative (DNDi), the Medicines for Malaria Venture, and the recent TB Alliance, have shown that non-traditional development pathways can lead to innovative treatments for immediate global public health needs [31]. The key is to preserve existing antibiotics R&D while creating sustainable market-based incentives to retain existing private investment and attract potential private investment. While in this regard awareness has improved the need to speed up the R&D of new antibiotics, the WHO revealed a decline in the clinical antibacterial pipeline against the priority pathogens listed in their 2017 analysis as only eight new antibiotics—one of which is for treatment of tuberculosis—have been approved [33]. This indicates that the antibacterial pipeline is insufficient and requires increased investment and additional initiatives to facilitate the necessary antibiotics R&D to ensure a robust pipeline [31].

4. Antibiotics and Gut Microbiota

The term “gut microbiota” refers to the collection of bacteria, viruses, and eukaryotes that inhabit the gastrointestinal tract [34]. The human gut microbiota is a host-specific ecosystem that to some extent can be inherited, matures critically in early life [35], and influences the host’s central physiological and pathophysiological mechanisms [34]. Gut microbiota have long been regarded as playing a key role in the gut’s normal functioning and overall human health [36]. Antibiotics have been shown to cause the gut microbiota to shift into temporally quasi-stable or alternate stable states, making it more tolerant to external influences [37,38]. This leads to post-antibiotic dysbiosis, which is marked by loss of diversity, loss of certain essential taxa, changes in metabolic capacity, and decreased colonization resistance against invading pathogens [34]. Gut dysbiosis aids the horizontal transfer of resistance genes, accelerating the evolution of drug-resistant bacteria and the spread of antibiotic resistance [39]. Antibiotic treatment has a significant impact on the overall taxonomic composition of gut microbiota, with profound compositional effects on luminal and mucosal bacteria leading to decreased taxonomic richness [37,40], as well as significant upregulation of resistance genes—even to non-administered drug classes [41,42], which can last for years [38,43]. The rate at which antibiotics are administrated is alarming, when put into the context of the reduced overall diversity of gut microbiota species including the loss of some important taxa. This causes metabolic shifts, increases gut susceptibility to colonization, and stimulates the development of bacterial antibiotic resistance [44]. For instance, antibiotics are among the top-selling drug classes in Germany, accounting for almost 38 million prescriptions in ambulatory care settings, with increased prescription of new broad-spectrum antibiotics and second-line drugs, such as cephalosporins and fluoroquinolones [44].

5. Traditional Medicine, Medicinal Plants and AMR

In a bid to address this growing public health threat as well as to stop our planet from progressing to the post-antibiotic era, much of the rapidly growing body of scientific publications on AMR supports a focus on medicinal plants as a promising source of potential new antibiotics to cope with infections caused by resistant bacteria pathogens, since about 25–50% of existing pharmaceuticals are plant-derived [45]. A precise definition of medicinal plants, otherwise known as medicinal herbs, has been provided from the discipline of ethnobiology. These can thus be defined as plant species with biologically active compounds used in traditional medicine for pharmacological and therapeutic purposes in humans and animals [46]. Historically, extracts of medicinal plants contained diverse chemically active phytochemicals and were generally recognized as safe (GRAS) at concoction dosage, without the side effects or resistance often associated with synthetic drugs such as Prontosil, Salvarsan, and purified penicillin. They may mark an important moment in the history of drug discovery research, thereby corroborating the validity of traditional medicine [46,47]. Over the years, the extraction, isolation, and identification of plants containing phytochemicals have led to the discovery of novel therapeutics in the pharmaceutical industry’s research and development (R&D) sector, resulting in a positive impact on the healthcare system. This can be evident in the treatment of cancer and other life-threatening diseases of public health concern. Consequently, since ancient times a plethora of plant extracts and biologically active compounds, i.e., secondary metabolites, have been widely identified and documented for use in traditional medicine either as dietary supplements, or for prophylactic or therapeutic use [48,49]. The pharmacopeia of renowned professional traditional medical systems has been formally accepted by the WHO traditional medicine strategy 2014–2023 [50]. This includes the Indian Ayurveda, i.e., traditional Indian medicine (TIM), traditional Chinese medicine (TCM), and Arabic Unani. These incorporations were achieved by integration of traditional medicine into national health systems by collaborating with Member States to develop national policies in their health sectors, necessary international guidelines, and methodologies for medical plant research into products, practices and practitioners [50]. This has contributed to the advancement of medicinal plants currently in use across the globe for the prevention and treatment of infections, through lists of beneficial naturally derived botanicals, plant products (leaves, barks, stems, roots), and the phytochemicals contained therein [48,49]. Curcumin—a natural polyphenol obtained from Curcuma Longa L.—has been used in traditional medicine as a dietary supplement in the treatment of infectious diseases, and has been widely studied for chemotherapeutic purposes [51]. Taxol—a highly powerful chemotherapeutic compound derived from the bark of the slow-growing Pacific yew tree Taxus brevifolia—is very active in the treatment of cancer [52]. However, the successes of traditional medicine can be improved through a close network of multidisciplinary collaborations with input from all sectors to further understand the mechanisms of medicinal plant products and those of traditional medicines that could lead to novel and super-active new compounds [53].

With regards to the application of medicinal plants on multi-drug resistant (MDR) pathogens, several reports of the antimicrobial activity of certain plants have been produced by researchers. In their study, Gupta and colleagues reported the antibacterial efficacy of Alpinia galanga (L.) against multi-drug resistance isolates of Mycobacterium tuberculosis [54]. The antimicrobial activity of extracts obtained from different medicinal plant parts including Smilax zeylanica, Trema orientalis, and Acacia pennata have been reported to exhibit a substantial bactericidal effect on the MDR-ESKAPE [55]. The recent discovery of Artemisinin, an antimalarial drug from the medicinal plant Artemisia annua, led to the rapid and effective treatment of chronic malaria infection through WHO-recommended Artemisinin-based combination therapies (ACTs). This is evidence of medicinal plants being a promising source for the development of novel antibiotics that can actively work against MDR pathogens [56,57]. Despite this success, WHO has reported that about half of the world’s population still lacks sufficient essential traditional medicine coverage—basically prepared from medicinal plants [58,59]. Recent estimates have shown that out of the 350,000 vascular plant species identified by science only 7% (~26,000) have been reported and documented for use as medicine [60]. While some of these documented medicines have been patronized in regions including Africa, the WHO alongside the Member States developed a set of tools and guidelines to augment and facilitate the development of African Traditional Medicines through proper identification of the active components of medicinal plants and their standardization for use [61,62,63]. Currently, plants are incorporated into global healthcare systems either for use in R&D as sources of novel pharmaceuticals or as traditional medicines [64,65]. For example, the WHO African region has guided the direction of the promotion of African Traditional Medicine through their Strategy of “Enhancing the Role of Traditional Medicine in Health Systems” [63]. Therefore, there is no doubt that the global demand for medicinal plant products poses a great risk and threatens the survival of well-known species, and over-exploitation could send biodiversity into spiraling decline. Evidently, out of the 25,906 plant species documented for medicinal use, a total of 25,791 non-hybrid species were analyzed by Medicinal Plant Names Services (MPNS), of which 5411 are on the IUCN (International Union for Conservation of Nature) Red List of Threatened Species and 723 are currently threatened [60,66,67]. However, the conservation risk associated with certain species of medicinal plants has been well reported in the literature. Most of the scientific publications on medicinal plant conservation de-emphasize plant endemism, with an overarching focus on conservation at the national level. This focus also extends to maintenance of species’ genetic diversity, which is not fully reflected in the current extinction classifications [68]. Nature has served as an important source of therapeutics needed to address the rising public health challenges of the 21st century [59]. In 2019 alone, about 1955 new species of plants were reported and these plants have the potential to yield active compounds essential in the development of new drugs [69,70]. The world’s biodiversity remains underexplored in the course of searching for new medicines essential for our health and well-being, as reported by MPNS [60]. More efforts are needed towards exploring biodiversity for potential active molecules from plants, as well as their scientific evaluation and analysis to determine their medicinal values without putting biodiversity at risk [59]. Recent developments in gene technologies have facilitated the act of biopiracy in countries with rich biotechnological tools but poor biodiversity [71]. This is usually done by illegally patenting the traditional knowledge of other countries, and addressing this issue requires bioprospection of medicinal plant species to protect the sovereign right of indigenous peoples to traditional medicine and biodiversity. Intellectual property (IP) protection is highly essential to the preservation of traditional medicinal plants, to enable their continued use for therapeutic purposes and also to protect biodiversity [72]. As soon as the medicinal value of plants is confirmed, the onus lies on the national authority to conserve such plants from human activities including deforestation, urbanization, and industrial development that could threaten the survival of the plants [72]. Thus, without IP protection for traditional medicine, it will be difficult to achieve—global sustainable use.

6. Planetary Health and Antimicrobial Resistance

The term “Planetary Health” refers to the interconnected vitality of natural and anthropogenic eco-systems that determine both human health and that of the Earth [73]. In other words, it describes how planetary ecosystems and human health are intertwined, each interdependent on one another [74]. In a bid to address the diverse threats to health caused by uncontrolled anthropogenic changes to our environment [73], the Rockefeller Foundation–Lancet Commission on Planetary Health clearly defined this concept as “the achievement of the highest attainable standard of health, wellbeing, and equity worldwide through judicious attention to the human systems—political, economic, and social—that shape the future of humanity and the Earth’s natural systems that define the safe environmental limits within which humanity can flourish” [73]. From this definition published in 2015, it can be understood that the health of humans is intertwined with that of the natural environment; humanity can only thrive in a flourishing environment with less pressure on the Earth’s natural systems. However, several researchers have established the positive correlation of AMR with anthropogenic activities, and the role of environmental compartments (soil, water, and air) in the spread of AMR [75,76]. A growing number of studies are beginning to show that the problem of AMR is associated with climate change—one of the greatest threats facing the biosphere of our planet [77,78]. All these challenges have shown that the threat of AMR is linked with human activities in the natural environment, requiring the inclusion of AMR in the Planetary Health agenda. As previously stated, environmental pollutants such as antibiotics residues, pharmaceutical compounds, and heavy metals have been reported to act as selective pressures on the ever-increasing ARGs in the soil. These can, in turn, be transmitted to humans through the direct food chain causing great impact on health; there is a need for more study of this issue [79]. Such pollutants, particularly antibiotics residues, have been reported to affect the functioning of the ecosystem through their impact on biogeochemical processes; unfortunately, there is also a paucity of research in this regard [80]. We therefore call for interdisciplinary collaboration between colleagues in the fields of environmental, animal, and human health to conduct eco-epidemiological research from a planetary health perspective with a view to understanding the effects of environmental factors and anthropogenic activities on antimicrobial resistance. The evidence-based results from this collaboration will guide the modification of existing interventions and the formulation of policies aimed at tackling the rising threat of antimicrobial resistance—for human health security and to safeguard the health of the planet [81,82,83].

7. Conclusions

Microbes have similar relationships with humans, animals, and plants. In the human gut, a diverse variety of microbial communities and their collective genome, referred to as the “microbiome”, serve distinct physiological tasks and play a key role in the immune system. Despite the potential ecosystem services of gut microbiomes for human and environmental health, they remain vulnerable to a variety of factors, including long-term antibiotic use, either directly or indirectly through antibiotic residues in the environment and food chain. This intersection of the environment, our internal world, and anthropocentric actions, prolongs risking the destruction of microorganisms beneficial to macro and microcosms. Frameworks for integrating traditional medicine into health systems must be standardized and synergized as part of a broader concept of “Planetary Health” that encompasses the vitality of personal and environmental health at all scales.