In recent years, medicinal plants have gained significant attention in modern medicine due to their accessibility, affordability, widespread acceptance, and safety, making herbal remedies highly valued globally. Consequently, ensuring medicinal plants’ quality, efficacy, and safety has become a critical concern for developed and developing nations. The emergence of multidrug-resistant microorganisms poses a serious global health threat, particularly in low-income regions, despite significant advancements in antimicrobial drugs and medical research over the past century. The rapid spread of these multidrug-resistant infections is primarily attributed to improper prescriptions, overuse, and unregulated access to antibiotics. Addressing these challenges, the standardization of plant-derived pharmaceuticals could pave the way for a transformative era in healthcare. Preserving and leveraging the historical knowledge of medicinal plants is essential before such valuable information is lost. Recently, there has been growing interest among natural and pharmaceutical scientists in exploring medicinal plants as potential sources of antimicrobial agents. This current review aims to identify the most common pathogens threatening human health, analyze the factors contributing to the rise of drug-resistant microorganisms, and evaluate the widespread use of medicinal plants across various countries as alternative antibiotics, highlighting their unique mechanisms of antimicrobial resistance.
In 1928, Alexander Fleming serendipitously discovered penicillin, the first natural antibiotic, marking the onset of antibiotic resistance in the early 20th century (1). This initial discovery catalyzed the advancement of further antibiotics, including streptomycin, chloramphenicol, erythromycin, and chlortetracycline, resulting in a “golden era” of antibiotic development from 1960 to 1980 (2). Nonetheless, the goals of the pharmaceutical sector have changed, resulting in a decrease in the discovery of novel antibiotics and an increase in antimicrobial resistance (AMR) (3). As a result, drug-resistant bacterial infections currently represent a considerable worldwide health risk (3, 4). The comprehensive antibiotic resistance database (CARD) includes more than 5,000 resistance sequences, with a restricted subset linked to notable diseases of concern (4). The problem is exacerbated by the slow pace of new effective antibiotic discovery (5).
AMR is a natural phenomenon in which microorganisms (bacteria, fungi, and protozoa) acquire the capability to endure and proliferate despite the administration of medications such as antibacterial, antifungal, and antiprotozoal antibiotics (6). Antibiotics are essential for addressing bacterial illnesses; however, their extensive application, particularly in resource-limited environments, generates selective pressure that fosters the development of resistance (7, 8). This results in heightened morbidity and death (8). The emergence of “superbugs,” which are resistant to many medications, highlights the gravity of the issue, leading the World Health Organization (WHO) to designate AMR as a significant global health challenge (7). Recent evidence reveals that AMR currently accounts for millions of fatalities annually, with forecasts indicating a substantial rise to 10 million deaths per year by 2050 (9).
The rise of antibiotic resistance poses a significant threat to global health, with methicillin-resistant Staphylococcus aureus (MRSA) serving as a prime example of a “superbug” contributing substantially to mortality from drug-resistant infections (10). Bacteria, among the earliest life forms on Earth, are ubiquitous, inhabiting both domestic and professional environments. While most bacterial species are harmless to humans, specific strains, including S. aureus, Helicobacter pylori, Escherichia coli, and Bacillus anthracis, can overcome host defenses and induce severe illnesses (10, 11). These infections can present as various diseases, including pneumonia, endocarditis, septicemia, and osteomyelitis, underscoring the broad pathogenic capabilities of these organisms (11, 12).
Healthcare-associated infections (HAIs) represent a persistent challenge to patient safety and public health, often leading to serious complications and placing a considerable burden on society (13). Conventional methods for preventing clinical infections have focused on aseptic techniques and systemic antibiotic treatments (13). However, these methods frequently fail to combat established infections effectively (14). A particularly striking example of this challenge is the treatment of infections associated with medical devices. Systemic antibiotic therapy for infections linked to devices such as catheters, artificial prosthetics, subcutaneous sensors, and orthopedic implants demonstrates a disappointingly low success rate, ranging from 22% to 37% (15). The restricted effectiveness highlights the challenge of eliminating established infections when foreign elements are present since they might facilitate bacterial colonization and biofilm development (15).
Furthermore, administering high doses of antibiotics, often necessary to treat localized infections, can harm surrounding tissues. Such high concentrations can lead to cytotoxicity and adverse reactions, further complicating treatment and potentially hindering patient recovery (16). The misuse of antibiotics may be even more alarming due to its contribution to the acceleration of bacterial drug resistance development and dissemination (17). The selective pressure exerted by frequent antibiotic exposure allows resistant strains to thrive, gradually diminishing the effectiveness of these crucial medications (17). This establishes a detrimental loop in which infections become progressively difficult to manage, hence intensifying the demand for elevated antibiotic dosages and aggravating the issue of resistance (17). The convergence of these factors - the rise of superbugs such as MRSA, the difficulties in treating device-related infections, and the adverse effects of high-dose antibiotic therapy - highlights the critical need for novel strategies to prevent and manage bacterial infections in the face of rising AMR (17).
Despite advancements in developing novel antimicrobial agents to address drug-resistant bacteria, such as antibacterial peptides, amphiphiles, and antimicrobial materials, including nanoparticles, hydrogels, engineered surfaces, and coatings, bacterial resistance continues to pose a substantial challenge (18). Current research efforts are, therefore, increasingly focused on developing strategies that can effectively eliminate bacteria without simultaneously driving the evolution and spread of further resistance (18). Consequently, it is imperative to identify novel antimicrobial treatment agents. In recent years, scientific and pharmaceutical communities have exhibited an interest in medicinal plants as potential sources of antimicrobial drugs. Employing selective screening of phytochemicals through medical data offers a dependable approach for identifying innovative medicines (19).
Chinese researchers identified artemisinin from Artemisia annua utilizing insights from traditional Chinese medical literature (20). This discovery has already led to the rescue of millions of individuals suffering from malaria (21). The WHO currently recommends a combination medication based on artemisinin as the treatment for this highly fatal disease. Currently, this medication is extensively utilized worldwide (22). Due to their historical effectiveness as anti-infective agents, plants historically employed for medicinal purposes may be crucial in identifying innovative therapeutics for diverse microbial illnesses (23–25). Ancient herbal treatments have been used for centuries to ease disorders and improve general well-being (26, 27). Typically, medicinal plants’ leaves, bark, roots, and flowers are amalgamated to produce an infusion (28, 29).
For example, compounds from the family Zingiberaceae, such as turmeric (Curcuma longa), and tamarind (Tamarindus indica), have been used to cure several diseases caused by pathogenic microorganisms, including diarrhea and dysentery (30, 31). Few studies have investigated the anti-infective properties of medicinal plants, despite numerous recent ethnobotanical surveys indicating their use by individuals to mitigate infectious ailments (32, 33). Many other studies have conducted targeted studies on the beneficial effects of compounds derived from medicinal plants, such as anti-Candida agents (34), anti-biofilm agents (35), and inhibitors of resistant microbial isolates (36).
The current review comprehensively examines the multidrug-resistant (MDR) microorganisms that present the greatest threat to human health. It analyzes the various causes contributing to antibiotic resistance and emphasizes the potential of medicinal herbs as a safe and efficient treatment.
In recent decades, microorganisms have increasingly resisted commonly used antibiotics (37, 38). Current medical concerns include not just infectious diseases such as avian influenza, human immunodeficiency virus (HIV), and severe acute respiratory syndrome (SARS) but also the emergence of resistant microorganisms that cause diseases that were previously eradicated, such as tuberculosis and malaria (39). In the past thirty years, the ineffectiveness of antibiotics and the absence of effective vaccinations have led to the demise of more than 25 million individuals, including over 5 million children (7).
Antibiotic resistance occurs when a bacterium becomes unresponsive to previously effective medications. Several frequently utilized antibiotics are now ineffective against 70% of the bacteria that cause nosocomial infections (40). Numerous mechanisms of medication resistance to various illnesses have been proposed, especially for the most commonly utilized pharmaceuticals (40). The modes of action of several antibiotics on Gram-positive and Gram-negative bacteria are illustrated in Figure 1.
Figure 1 The mechanisms of action of several antibiotics on Gram-positive and Gram-negative bacteria. Gram-positive bacteria, characterized by a thick peptidoglycan layer and teichoic acids, are vulnerable to antibiotics such as glycopeptides (e.g., vancomycin) that impede cell wall formation and daptomycin, which affects membrane potential. Gram-negative bacteria, characterized by an outer membrane and a thinner peptidoglycan layer, exhibit lower permeability yet remain susceptible to polymyxins that compromise the outer membrane and other agents that affect ribosomes (protein synthesis) or DNA gyrase (DNA replication). Both types exhibit analogous vulnerabilities in protein synthesis, folic acid metabolism, and DNA replication, which are targeted by antibiotics such as tetracyclines, sulfonamides, and quinolones, respectively. Resistance mechanisms are also demonstrated, including modified penicillin-binding proteins, beta-lactamase synthesis, efflux pumps, and porin alterations.
The improper use of antibiotics has been demonstrated to increase the development and spread of drug-resistant microorganisms (41). Inadequate systems for ensuring the quality and continuous supply of medications, coupled with ineffective surveillance and monitoring mechanisms, along with insufficient control and preventive measures, have substantially facilitated the rise of antibiotic resistance, especially in developing nations where policies are deficient (41). Comprehending how these detrimental organisms evade treatment is essential for formulating alternatives or preserving the effectiveness of current antimicrobial therapies. The spread of antibiotic resistance through foods is depicted in Figure 2.
Figure 2 Antibiotic resistance spread through foods. Animal-derived foods, such as dairy, meat, and poultry, provide the principal source of most foodborne microbial diseases. The improper use of antimicrobials in agriculture contributes to resistance.
