Mining Bioactive Compounds against Drug-Resistant Microorganisms from Ethnomedicine: Examples of 32 Ethnic Medicines in Yunnan

INTRODUCTION

The overuse of antibiotics has led to the irreversible emergence of Multidrug-Resistant Organisms (MDROs), including so-called “superbugs” (Honigsbaum, 2018) and “super fungi” (Pappas et al., 2018). In 2019, bacterial infections-both MDROs and antibiotic-sensitive-became the second leading cause of mortality worldwide after ischemic heart disease, accounting for approximately 7.7 million deaths directly attributed to bacterial pathogens (Wang, Z.-J. et al., 2024). Among them, Methicillin-Resistant Staphylococcus aureus (MRSA) alone was responsible for over 100,000 deaths (Collaborators, 2023). That same year, Antimicrobial Resistance (AMR) contributed to an estimated 4.95 million deaths globally (Tang et al., 2024; Vos et al., 2020), with projections indicating that this figure could rise to 10 million annually by 2050 (Wang, Z.-J. et al., 2024; Wang, Z.-J. et al., 2024; Wei et al., 2024). Epidemiological studies show that MRSA and Vancomycin-Resistant Enterococcus (VRE) are the most prevalent pathogens causing hospital-acquired infections (Shi, N. et al., 2024). In recognition of the growing threat to public health, the United States Centers for Disease Control and Prevention (CDC) classified both MRSA and VRE as “serious threats” in its 2019 Antibiotic Resistance Threats Report. With the emergence of COVID-19 as a global pandemic, co-infections became increasingly common: over half of critically ill patients were found to harbor concurrent bacterial or fungal infections, and more than 30% of COVID-19 patients developed secondary bacterial infections (Caiazzo et al., 2022). Alarmingly, MDROs were detected in up to 80% of these co-infections (Kreitmann et al., 2023). In the post-pandemic era, the acceleration of bacterial resistance driven by COVID-19 has elevated long-standing concerns into an urgent global crisis (Hsu, 2020). As a result, the development of novel therapeutic agents targeting MDROs has become imperative.

Over the past two decades, only five novel classes of antibacterial agents with distinct chemical structures-cyclic lipopeptides, oxazolidinones, teixobactins, pleuromutilins, and diarylquinolines-have been approved for clinical use (Cook and Wright, 2022). However, clinical strains resistant to these drugs have already emerged. Developing a new antibiotic typically requires over a decade, while bacterial resistance can develop within just 1-2 years, raising the alarming prospect of a future with no effective antibiotics for humans (Macesic et al., 2025). Bacterial resistance is a survival strategy driven by microbial adaptation to antibiotics (Wang, Z. et al., 2018). The issue of antibiotic resistance reflects shifts in ecologic niche overlap and competitive dynamics within microbial communities, involving trade-offs in resistance costs and the persistence of resistant pathogens (Silva et al., 2016). While resistance has coexisted with antibiotics of microbial origin (Porras et al., 2021), Natural Products (NPs) may offer advantages in overcoming resistance due to their unique structures (Porras et al., 2021), mechanisms of action (Kumar and Engle, 2023), and targets (Porras et al., 2021; Woo et al., 2023), which differ from conventional antibiotics (Wang et al., 2019).

In response to the urgent global demand for novel antimicrobial agents, mining antimicrobial bioactive compounds from traditional medicinal plants is an effective method. Our previous research found that itchy-sore ulceration (Wang et al., 2020), stomachache (Wang et al., 2023), upper respiratory tract infection (Wang et al., 2021), vomiting (Wang et al., 2021), diarrhea (Zhu et al., 2021), strains (Ma et al., 2022), beriberi (Xu et al., 2022), shigellosis (Wang, Z.J. et al., 2024), scald (Zeng et al., 2022), dyspepsia (Tang et al., 2024), conjunctivitis (Luo et al., 2023), gastralgia (Wen-Biao et al., 2024), pharyngitis (Chen et al., 2024), gonorrhea (Wen-Biao, 2024), pertussis (Liu et al., 2024), common cold (Shen et al., 2024), phthisis (Luo et al., 2024), scabies and tinea (Luo-EE et al., 2024), chronic tracheitis (Shi et al., 2024), skin infections (Shi, Y.-Z. et al., 2024), and tetanus (Zhou et al., 2024) of botanical drugs contain compounds with anti-MDROs activity. These findings encouraged us to revisit key traditional pharmacopoeias, including the Dictionary of Chinese Ethnic Medicine, Essentials of Chinese Ethnic Medicine, and ZhongGuo MinZu YaoZhi Yao, to further explore the ethnomedical basis of these treatments.

Literature Search Strategy

A comprehensive literature search was conducted using multiple databases, including SciFinder, Google Scholar (https://sci.673.org/index.html), Scopus (Elsevier), Medline, Web of Science, X-MOL (www.x-mol.com), PubMed, and the China National Knowledge Infrastructure. The search targeted publications related to the Latin names of the 32 selected plant species, as well as their reported antimicrobial properties, inhibitory concentrations, activities against MDROs. In addition, local records, monographs, and non-English-language journals were reviewed to supplement the database search (up to March 2025).

Plant Characteristics

Geographic Distribution

The symptoms corresponding to these traditional uses are summarized in Table 1. Based on this ethnobotanical survey, we investigated the traditional applications of ethnic medicinal plants and their associated antibacterial bioactive compounds. We found that the folk usage of 32 ethnic medicinal plants implies the presence of compounds with activity against MDROs. This review systematically examines the antibacterial chemical constituents, synergistic interactions, mechanisms of action, and pharmacological properties of 32 representative medicinal plant species from Yunnan Province and their derived NPs, covering research published between 2000 and 2025.

32 plant names, including Morus alba, Scoparia dulcis, and Cannabis sativa are listed in Table 1. These NPs active against MDROs mainly comprise over 160 bioactive compounds, including oxylipins, alkaloids, resorcinol terpenoids, triterpenoid saponins, cannabinoids, and isopentenyl flavonoids.

Correlation Analysis Between Traditional Use and Anti-MDROs Activity

The traditional uses of the selected medicinal plants were categorized into various traditional application domains. There are, hypertension, diabetes mellitus, itchy-sore ulceration, cephalalgia, nephritis, sore throat, scabies, shigellosis, eczema, beriberi, scald, tonsillitis, ascites, gastralgia, influenza, conjunctivitis, menorrhagia, dyspepsia, hepatitis, bronchitis, tussis, diarrhea, skin pruritus, head trauma, pyrexia, toxic heat, deficiency heat, rubeola, pertussis, varicella, hematuria, gastric and oral ulcers, rheumatic arthralgia, weakness, soreness of the waist and knees, heating-clearing and toxicity-removing, diuretic, persistent headache, ocular pain, carbuncle, cystitis, malaria, upper respiratory tract infection, pneumonia, urticaria, herpes zoster, joint stiffness, foot edema, vomiting, infection, gonorrhea, swelling-reducing, detoxification, antibacterial effect, enteritis, injuries, dysentery, pulmonary tuberculosis, tetanus, insecticidal antipruritic, rheumatoid arthritis, traumatic injuries, fracture, anti-inflammatory, and gynecologic diseases. A correlation analysis was then performed between their traditional uses and anti-MDROs activity. Frequency data for each application category and corresponding antimicrobial activity were analyzed using origin software, and the results were visualized in a correlation diagram (Figure 1).

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Characteristics of 32 Ethnic Medicinal Medicines

Yunnan Province, recognized as China’s most botanically diverse region, is widely known as the “Kingdom of Plants” (Zhao Mingxu et al., 2024), the “Kingdom of Animals” (Yi, 2014), and the “Kingdom of Wild Fungi” (Committee, 2016). These reputations are attributed to its unique geographic and climatic diversity, as well as its rich traditions in ethnic medicine. However, the region also faces several challenges, including low rates of technological transformation, tensions between resource conservation and exploitation, and a lack of standardization in medicinal plant practices (Zhang Xuejia et al., 2023). This review compiles detailed botanical profiles of 32 ethnic medicinal plant species, which can be categorized into herbaceous plants, shrubs, and trees based on their traditional uses, bioactive constituents, and demonstrated antimicrobial activity. For each species, information is provided on their origins and distribution in China, ecological growth conditions, altitude ranges, and key morphological features of stems, leaves, flowers, and fruits. A summary of these characteristics is presented in Tables 1 and 2.

Correlation Between Ethnomedicinal Practices and Antibacterial Properties

As one of the most bio-diverse and ethnoculturally rich regions in China, Yunnan is home to extensive traditional medicinal practices deeply rooted in its ethnic minority communities (L I Yao et al., 2020). The indigenous knowledge embedded in these ethnic medicines reflects unique ethnopharmacological traditions and has increasingly attracted scientific interest for their antibacterial potential (Wang et al., 2021; Wang et al., 2020). For example, the De’ang people use C. sativa to treat toothaches, with cannabinoids identified as its active antimicrobial constituents (Yadav et al., 2023). The Dai people use M. alba (Sangbaipi) to manage itchy sores and ulcerations (Jia Min-Ru and Yi, 2010), where the active compound morusin has been shown to exhibit activity against MDROs by disrupting bacterial cell membranes (Yadav et al., 2023). Both the Yi and Bai ethnic people apply P. polyphylla (Dianchonglou) to clear heat and toxins (Jia Min-Ru and Yi, 2010; Min-Ru, 2005), with its steroidal saponins demonstrating antibacterial effects via inhibition of key bacterial enzymes (Tagousop et al., 2018). In the Yi community, L. pterodonta (Choulingdan), a traditional anti-inflammatory herb, is used to treat respiratory infections and has been found to contain sesquiterpene lactones with pathogen-suppressing properties (Liu et al., 2007). Moreover, 95% ethanol extracts from widely used ethnomedicinal plants-such as H. cordata (Yuxingcao), M. haplocalyx (Bohecao), and P. vulgaris (Xiakucao)-have shown inhibitory effects against MRSA (Karthikeyan et al., 2020).

These examples highlight the value of integrating ethnomedicinal knowledge with modern biotechnological approaches to accelerate the discovery of plant-based anti-infective agents (Wang et al., 2021). However, diseases related to the digestive, respiratory, endocrine, nervous, and musculoskeletal systems, as well as conditions affecting the skin and facial regions, have often been overlooked in the past studies, primarily because they were not directly associated with MDROs infections. Although infectious diseases are most commonly associated with MDROs infections, our analysis suggests that a wider spectrum of disease categories also deserves attention. Numerous plant-derived compounds have been applied in treating ailments beyond classical infectious diseases. As shown in Figure 2A, antibacterial relevance was observed across various systems, including the digestive, respiratory, urinary, immune, cardiovascular, endocrine and metabolic, neurological, musculoskeletal, dermatologic, sensory organs, trauma-related, gynecologic, and diseases categorized under Traditional Chinese Medicine (TCM). The correlation between the traditional ethnomedicinal uses of these plants and their antibacterial properties is illustrated in Figure 2B and detailed in Table 2. Specifically, Table 2 summarizes the ethnomedicinal applications of 32 plant species reviewed here. Traditional uses for conditions such as itchy sores and ulcerations, stomachaches, upper respiratory tract infections, vomiting, diarrhea, sprains, strains, beriberi, shigellosis, heat-clearing and detoxification, scalds, dyspepsia, conjunctivitis, gastralgia, pharyngitis, gonorrhea, pertussis, common colds, phthisis, scabies, tinea, chronic tracheitis, and tetanus are likely associated with microbial infections. These patterns provide meaningful directions for future research into the antibacterial mechanisms and bioactive compounds targeting MDROs.

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Antimicrobial Compounds

Overview

In this review, 32 plant species were identified as exhibiting antibacterial activity, with 30 demonstrating efficacy against MRSA, VRE, and Candida albicans. Over the past three decades, the development of new antibiotics-particularly those targeting Gram-negative bacteria-has been severely limited. Today, we may find that existing treatments are increasingly inadequate in addressing emerging resistance mechanisms, and antimicrobial resistance, especially multidrug resistance, has escalated into a major challenge for clinical therapy (Wang, Z.-J. et al., 2024). Given that resistance among Gram-negative bacteria has become a global public health crisis (Apostol and Collaborators, 2024; Macesic et al., 2025), compounds with Minimum Inhibitory Concentration (MIC) values ≤ 64 µg/mL against Gram-negative strains were also catalogued. These included 87 phenolics and their derivatives, 48 terpenoids and derivatives, 8 alkaloids and derivatives, 6 oxylipins, and 11 other types of metabolites. In total, over 160 compounds with activity against MRSA, VRE, C. albicans, and Gram-negative bacteria were isolated from approximately 32 ethnomedicinal plant species. Phenolics and their derivatives, terpenoids and derivatives, alkaloids and derivatives, oxylipins, and other metabolites accounted for 54.4% (87), 30% (48), 5% (8), 3.8% (6), and 6.8% (11) of the total compounds, respectively. The botanical origins, chemical structures, antimicrobial activities against MDROs, and structure-activity relationships of these plant-derived NPs are discussed in detail below. A summary of the antimicrobial bioactivities of these NPs against MDROs and Gram-negative bacteria is provided in Table 3.

Phenolics and Their Derivatives

Phenolic secondary metabolites are key functional bioactive compounds produced by plants during their growth and development (Kumrungsee et al., 2023). In this review, NPs with antibacterial activity include simple phenols, phenylpropanoids, xanthones, flavanones, resorcinols, quinonoids, isoflavones, lignans, chalcones, tannins, flavanonols, flavan-3-ols, among others. The basic structural classes of phenolics are illustrated in Figure S1.

Chlorogenic acid (3), isolated from C. speciosa and O. gratissimum, has been reported to exhibit antibacterial activity against Streptococcus pneumoniae, S. aureus, Bacillus subtilis, Shigella dysenteriae, and Salmonella typhimurium, with MICs ranging from 20 to 40 μg/mL (Ugbogu et al., 2021). Chlorogenic acid (3) displays broad-spectrum activity against both Gram-positive and Gram-negative bacteria. Several phenylpropanoids isolated from M. alba, including moracin C (6), mulberrofuran B (7), albafuran A (8), moracin G (9), mulberrofuran G (12), mulberrofuran K (13), albanol B (14), and mulberrofuran Q (15), exhibit anti-MRSA activity with MICs ranging from 2 to 16 μg/mL (Zhu et al., 2021; Zhu et al., 2024). Additionally, flavonoid compounds such as 18-21, 25-26, and 41-43, also from M. alba, demonstrate potent activity against MDROs, with MICs in the same range (Zhu et al., 2021; Zhu et al., 2024). Moreover, kuwanon O (43) has been shown to inhibit the MRSA efflux pump (Zhu et al., 2021), while morusin (20) targets bacterial inner membrane phospholipids, disrupts membrane integrity, and induces the generation of Reactive Oxygen Species (ROS) (Zhu et al., 2024). These mechanisms differ from those of conventional antibiotics and suggest a lower likelihood of inducing resistance development.

Flavonoid derivatives have a wide range of antibacterial and antioxidant activities. Daphnin (16) is isolated from S. viridis (Cottigli et al., 2001; Gong Jiang et al., 2010), while xanthotoxin (17), obtained from Z. khasianum, shows antibacterial activity against S. aureus and Methylococcus luteus with MIC 30 µg/mL (Walasek et al., 2015; Wang et al., 2021). Based on structural analyses of compounds such as α-, β-, and γ-mangostin, cratoxylone, gambogenic acid, neo-morellic acid (22), gambogic acid (23), neogambogic acid (24), and related derivatives, Tang et al., (2024) identified hydroxyl groups, isopentenyl substituents, and carboxyl groups at the C-5 position as key contributors to antibacterial activity against VRE. Further mechanistic studies demonstrated that morellic acid (22) binds to phosphatidylglycerol in the bacterial inner membrane, disrupting the proton motive force and membrane rigidity. This disruption causes oxidative stress via the accumulation of ROS, ultimately resulting in bacterial cell death (Tang et al., 2024). Transcriptomic analyses further linked these effects to perturbations in glycerophospholipid metabolism and fatty acid biosynthesis pathways. Notably, morellic acid exhibits dose-dependent eradication of up to 80% of mature VRE biofilms, with efficacy comparable to that of ampicillin, used as a positive control. These findings highlight the promise of structural optimization in enhancing antimicrobial agents against resistant pathogens (Tang et al., 2024).

Additional flavonoid derivatives-including linarin (27), cirsimarin (28), luteolin (31), sappanone B (37), (8,3′-diprenyl-5,7,4′-trihydroxyflavanone (40), phloretin (44), aromadendrin (45), genistin (46), 4-hydroxyboesenbergin B (49), and galangin (50)-are isolated from S. dulcis, C. trichosphaera, C. sappan, F. prostrata, L. polystachyus, S. viridis, and A. japonica, respectively. Among these, linarin (27) exhibits particularly potent activity against S. aureus, with a MIC as low as 0.38 µg/mL (Davoodi et al., 2022). Although luteolin (31) exhibits an MIC of 32 µg/mL against MRSA, it showed synergistic effects when combined with gentamicin (Qiu et al., 2011). Kaempferol derivatives (32-35) have demonstrated activity against P. aeruginosa and are found to disrupt the bacterial surface structure (Ugbogu et al., 2021; Xu et al., 2022). Phloretin (44), isolated from L. polystachyus, has been reported to possess broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria, with MIC values ranging from 32.4 to 100 μg/mL (Park et al., 2012; Shang et al., 2022; Wang, G. et al., 2018). It targets E. coli biofilms and inhibits the expression of the virulence factor sortase B (SrtB). Galangin (50) has been shown to suppress bacterial toxin production (Lee et al., 2008; Ma et al., 2017).

Cannabinoids (51, 52) have demonstrated potent antibacterial activity against MDROs, particularly MRSA and VRE, with MIC values ranging from 1 to 8 μg/mL (Appendino et al., 2008; Schofs et al., 2021). Alpininone (57) exhibits activity against VRE with an MIC of 32 μg/mL (Giang and Son, 2007). Resorcylic acid derivatives (58-61), isolated from the L. genus, show strong antibacterial effects against MRSA and VRE (MICs = 2-8 μg/mL) (Shi, N. et al., 2024). Mechanistic studies reveal that these compounds disrupt biofilm formation and damage the bacterial membrane by inducing metabolic imbalance. SAR analyses indicate that the presence of lipophilic long carbon chains at C-5/C-6 and hydrophilic hydroxyl/carboxyl groups are essential for anti-MRSA and anti-VRE activity.

The compound 1,7-bis-(4′- hydroxy- 3′- methoxyphenyl) - 5(R) - methoxyheptan - 3 - one (62) exhibit antibacterial activity against various Gram-negative bacteria, with an MIC of 71.2 μg/mL (Liang Hui et al., 2022). Grevillol derivatives (63-66), also derived from Lysimachia, display MIC values of 4-8 μg/mL against both VRE and MRSA (Chen Li Li et al., 2024; Shi, N. et al., 2024). Curcusinol (67), isolated from C. baccans, exhibit similar activity against MRSA with MICs of 4-8 μg/mL (Liu et al., 2024). Brazilin (68) and brazilein (69), isolated from C. sappan, exhibit synergistic effects with aminoglycoside antibiotics-brazilein with hygromycin B-against MDROs (Lee et al., 2014; Nirmal and Panichayupakaranant, 2014; Xu and Lee, 2004). Brazilin (68) is also found to inhibit bacterial protein synthesis (Zuo et al., 2014). Protosappanin A (70) and protosappanin B (71) show synergistic effects with gentamicin and amikacin against MRSA (Zuo et al., 2015). Phloroglucinol trimers (74-77), isolated from R. tomentosa, demonstrate potent anti-MRSA activity with MICs ranging from 0.5 to 2 μg/mL (Luo et al., 2023).

Terpenoids and Derivatives

Terpenoids, a diverse group of NPs, are structurally defined by their isoprene unit framework, with Mevalonic Acid (MVA) serving as a central precursor in their biosynthetic pathways. Their classification hinges on the count of isoprene units, leading to subcategories such as monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids, and triterpenoids.

Sesquiterpenoids and monoterpenoids are major constituents of plant volatile oils and are important raw materials in the fragrance and pharmaceutical industries. Sesquiterpenoids consist of three isoprene units (15 carbon atoms) and are biogenetically derived from farnesyl pyrophosphate. The MICs of anti-MRSA activity of Δ⁹-tetrahydrocannabinol (79), cannabichromene (80), cannabidivarin (81), and other cannabinoids (82-85) are1-8 μg/mL (Appendino et al., 2008; Berardo et al., 2024; Russo et al., 2021; Schofs et al., 2021). They are isolated from C. saliva, with potent activity against MRSA and Methicillin-Susceptible Staphylococcus aureus (MSSA) (Yang et al., 2022). The MIC of anti-MRSA of 4-epi-scopadulcic acid B (86) is 125 μg/mL (Phan et al., 2006). Capitachromenic acid E (87) and grifolic derivatives (88, 89), isolated from R. rubiginosum, display activity against MRSA and VRE with MICs ranging from 8.33 to 24.4 μg/mL (Luo-EE, 2024). Rhododaurichromanic acid A (90), derived from R. spinuliferum, exhibits broader antibacterial activity with an MIC of 5.37 μg/mL (Luo et al., 2024).

Aromadendrene (91) demonstrates anti-MRSA activity when combined with 1,8-cineole (Mulyaningsih et al., 2010). The against MRSA and VRE activities of (+)-15, 16-epoxy-8(17), 13(16), 14-labdatriene (93) are 32 μg/mL (Ma et al., 2017). Spinulinoid A-C (94-96), also isolated from R. spinuliferum, demonstrate antibacterial activity against VRE and MRSA with an MIC ranging from 2.7 to 5.37 μg/mL (Luo et al., 2024). E-confluentin (97), Z-confluentin (98), and anthopogochromene C (99), isolated from R. rubiginosum, demonstrate anti-MRSA and anti-VRE activities with MICs between 3.07-18.4 μg/mL (Luo-EE, 2024). Ferruginol (100), 19-hydroxyferruginol (101), sugiol (102), and 6α-hydroxydemethylcryptojaponol (103), isolated from C. trichosphaera, exhibit antimicrobial activity against MRSA and VRE, with MICs ranging from 4 to 32 μg/mL (Lu et al., 2025). Ferruginol (100) has been shown to modulate membrane permeability and fluidity in MRSA, leading to membrane depolarization and subsequent structural disruption (Lu et al., 2025). 14-deoxycoleon U (104), cativic acid (105), and cartrisine B (106), isolated from C. trichosphaera, show against MRSA activities with MIC 16-32 μg/mL (Lu et al., 2024; Lu et al., 2025). Research has found that cartrisine B (106) shows synergistic effects with tetracycline against MDROs (Joshi et al., 2021). A series of 16β-hydro-ent-kauran-17,19-dioic acid derivatives (107-110) demonstrate potent anti-MRSA activity, with MICs ranging from 0.12 to 0.5 μg/mL (Yang et al., 2016). Sigesbeckin A (111) and 18-hydroxy-kauran-16-ent-19-oic acid (112), isolated from S. orientalis, show synergistic effects with vancomycin and doxorubicin, respectively (Zhou et al., 2024). Their mechanism involves disruption of bacterial membrane integrity, contributing to their activity against MDROs. Cryptotanshinone (113), przewaquinone (114), and miltirone (115), isolated from Salvia miltiorrhiza and S. przewalskii, exhibit broad-spectrum activity against MRSA, MSSA, and VRE, with MICs ranging from 0.9 to 8 μg/mL (Huang-Huan, 2024; Zhong et al., 2021). In addition to antibacterial activity, compounds such as spinulinoids A-C (94-96), confluentins (97-99), 14-deoxycoleon U (104), and miltirone (115) are reported to inhibit the biosynthesis of key biofilm components by down-regulating biofilm-associated genes. Furthermore, cryptotanshinone (113) and przewaquinone (114) inhibit bacterial pyruvate kinase, interfering with energy metabolism in MRSA and MSSA (Zhong et al., 2021). Macrocarpal B (116), isolated from Eucalyptus spp., exhibit anti-MRSA activity with an MIC of 2 μg/mL (Jiang et al., 2025). Additionally, oleanolic acid (117), ursolic acid (118), and betulinic acid (119), obtained from L. polystachyum and C. speciosa, exhibit antimicrobial activity against MRSA, with MICs ranging from 2 to 64 μg/mL (Lei Ming et al., 2017; Wang et al., 2021). Olean-9(11),12-dien-3-O-palmitate (120) inhibit the growth of Bacillis subtilis and S. aureus with effective concentrations of 50-75 μg/mL (Zhao et al., 2012). The MIC of anti-C. albicans of prosapogenin CP4 (121), epipachysamine D (141), pachysamine M (142), sarcovagine D (148), and hookerianamides O (149) is 16-30 μg/mL (Duan et al., 2025; Shen et al., 2024; Wen-Biao, 2024). Lupeol (122) inhibits Sporothrix schenckii, Microsporum canis, and Aspergillus fumigatus with MICs 12-93.5 μg/mL (Kgosiemang et al., 2025). Additionally, α-amyrin (123) and β-amyrin (124) inhibit Candida krusei and C. albicans with MIC 30-125 μg/mL. These compounds show great capacity to resist pathogenic fungi of both animal and plant origin (Johann et al., 2007; Kgosiemang et al., 2025). The MIC of anti-MRSA or VRE of 3β-friedelinol (125), friedelin (126), celastrol (128), wilforol A (129), regeol C (130), 6-ethanoltriptohypol C (131), orthosphenic acid (132) ranges from 2 to 32 μg/mL (Ogunnusi et al., 2010). Betulin (127) can clear MRSA biofilms with less likely to cause drug-resistance in bacterial (Zhou et al., 2021).

The MIC of 3, 4-seco-cycloartane derivatives 1 (133), lithocarpic acid D (134), lithocarpic acid F (135), coccinetane B (136), lithocarpic acids I (137), against various bacteria (S. aureus, S. epidermidis, M. luteus, B. subtilis) ranges from 3.1 to 32 μg/mL (Fan et al., 2016; Tian-Tian, 2020). The MIC of anti-MRSA of 6α-O-[β-D-xylopyranosyl-(1→3)-β-D-quinovopyranosyl]-(25S)-5α-spirostan-3β-ol (138) is 4 μg/mL (Shi, Y.-Z. et al., 2024). Wattigenin C (139) inhibits Rhizopus stolonifera with the rate of 90%. Additionally, (25R, S)-ruscogenin (140) shows anti-VRE activity with an MIC of 10 μg/mL.

Alkaloids

Alkaloids represent one of the most important elements in plant secondary metabolites, with many alkaloids showing excellent antibacterial activity. A series of alkaloids, such as the 6-acetonyl-dihydronitid-ine (143), 6-acetonyl-dihydrofagaridine (144), 6-acetonyl-dihydrochelerythrine (145), dihydrochelerythrine (146), schinifoline (151), γ-fagarine (152), and neoechinulin A (153) have been isolated from the Zanthoxylum genus, exhibiting anti-MRSA activity with MICs ranging from 8 to 128 μg/mL (Ombito, 2021; Wang et al., 2021). Among them, compound (143-145) exhibits antibacterial activity against S. aureus with MIC 8-16 μg/mL and were found to inhibit efflux pumps of MRSA (Zeng et al., 2022). The compound γ-sanshoöl (147) also shows antibacterial activity against C. albicans with an MIC of 32 μg/mL; it can destroy the biofilm of fungi (Ma et al., 2022). Antofine (150), isolated from C. forrestii, shows antibacterial activity against Penicillium, E. coli and MRSA, with MIC ranging from 3 to 10 μg/mL (Qu et al., 2013).

Other Metabolites

In addition to the plant NPs discussed above, notable antibacterial and antifungal activities against MDROs and C. albicans have also been identified in several other compound classes, including fatty acids, phenylpropanoids, phyto-oxylipins, and miscellaneous metabolites (see Table 3 for details). Phenylpropanoid, isolated from A. tatarinowii and O. gratissimum, shows anti-MRSA and C. albicans activities with an MIC of 100 μg/mL. Heptacosan-1-ol (154), isolated from E. royleana, shows anti-fungal activity against C. albicans with MIC 15 μg/mL (Salehi et al., 2019). Siegeooxvlipin A-G (155-160), a compound of oxylipins isolated from S. orientalis, shows anti-MRSA activities, with an MIC ranging from 4-8 μg/mL (Zhou et al., 2025). These compounds functions as anionic surfactant, contributing to bacterial membrane disruption.

Mechanisms of plant-derived NPs against MRSA, VRE, and C. albicans

O-Coumaric acid (1) inhibits the expression of the T3SS gene in MRSA, thereby suppressing the biofilm synthesis pathway (Abdelkhalek et al., 2018). The antibacterial mechanism of antibiotics is to inhibit cell wall and protein synthesis, interfere with nucleic acid metabolism, and damage the outer membrane of gram-negative bacteria (Eliuz et al., 2022). These antibacterial mechanisms can easily lead to bacterial resistance. In this article, β-asarone (4), morusin (20), gambogic acid (23), neogambogic acid (24), kuwanon O (43), 4-hydroxyboesenbergin B (49), 8-hydroxycannabinol (51), cannabinol (52), 5-Dodecyl-1,3-benzenediol (63), ellagic acid (73), capitachromenic acid E (87), rhododaurichromanic acid A (90), (+)-15,16-Epoxy-8(17),13(16),14-labdatriene (93), spinulinoid A-B (94, 95), E-confluentin (97), Z-confluentin (98)，anthopogochromene C (99), macrocarpal B (116), ursolic acid (118), betulin (127), wilforol A (129), regeol C (130), grifolic (145), γ-sanshoöl (147), schinifoline (151), and γ-fagarine (152) are included. They demonstrate the ability to inhibit the biofilm formation and disrupt formed biofilms of MDROs, particularly MRSA, VRE, and C. albicans (shown in Figure 3) (Tang et al., 2024; Wang et al., 2020; Wei et al., 2024; Zhou et al., 2024; Zhu et al., 2021; Zhu et al., 2024).

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4-Hydroxyboesenbergin B (49) inhibits the expression of AtlA, SgrA, GelE, and Ace-key genes involved in biofilm formation in VRE-and exhibits anti-VRE activity without promoting drug resistance (Ma et al., 2017). Sevral plant-derived compounds, including xanthotoxin (17), morusin (20), morellic acid (22), pentagalloylglucose (72), cannabidivarin (81), cannabigerol (82), cannabichromenic acid (84), cannabidiolic acid (85), ferruginol (100), 19-hydroxyferruginol (101), sugiol (102), 14-deoxycoleon U (104), cativic acid (105), macrocarpal B (116), ursolic acid (118), 1,8-cineole (123), 3β-friedelinol (125), (25R, S)-ruscogenin (140), and siegeooxvlipin A-G (155-160) act primarily on bacterial membranes, including the inner membrane, outer membrane, and plasma membrane. And they alter membrane permeability, damage membrane structure, inhibit membrane function, and disrupt bacterial appearance, thereby exerting activity against MDROs (Tang et al., 2024; Zhou et al., 2025; Zhu et al., 2024).

Phloretin (44) targets and inhibits the pathogenic factor SrtB, thereby preventing the formation in Gram-negative bacterial (Shang et al., 2022; Wang, G. et al., 2018). Cannabidiol (83) interferes with bacterial cell division by stimulating diaphragm formation and suppressing the expression of the essential division gene ezrA, showing MIC values of 4-8 μg/mL against MRSE, Listeria monocytogenes, and Enterococcus faecalis (Schofs et al., 2021). Oleanolic acid (117) inhibits the expression of bacterial resistance proteins, including NDM-1, H1a, and β-lactamases, and exhibits broad-spectrum antibacterial activity (Yong-Lin, 2021). Celastrol (128) suppresses deoxyribonucleic acid synthesis by binding to P5CDH in MRSA (Yuan et al., 2023).

Oleanolic acid (117) and prosapogenin CP4 (121) exhibit synergistic antifungal activity against fungi by inhibiting the fungal cell wall synthesis pathway (Wen-Biao, 2024). These two compounds, along with sarcovagine D (148), demonstrate potent activity against C. albicans and are less likely to cause drug resistance (Shen et al., 2024). Sarcovagine D (148) disrupts mitochondrial membrane potential and induces ROS generation, ultimately promoting the death of C. albicans (Shen et al., 2024).

CONCLUSION

This paper reviews the botanical characteristics, phytochemistry, ethnobotanical applications, and antimicrobial activities of 32 ethnic medicinal plants from Yunnan. Current research primarily centers on the pharmacological activities of crude extracts or fractions. While known bioactive constituents include terpenoids, flavonoids, alkaloids, and polyphenols, the discovery of novel active compounds remains limited and requires further investigation. It is also evident that there is a lack of research methodologies integrating traditional usage, standard practices of bioactive ingredients isolation, and evaluation against MDROs. The mechanisms underlying their antimicrobial actions have not been fully elucidated. Although some studies have examined the mechanisms of action of plant-derived NPs against MRSA, VRE, and C. albicans, such investigations remain relatively superficial. Fewer than 10% of the previous studies have proposed potential molecular targets or pathways, as revealed by metabolomic, transcriptomic, and network pharmacology analysis. Comprehensive methodological frameworks to explore the mechanisms of plant NPs against MRSA, VRE, and C. albicans are still wanted. These mechanisms need to be validated using molecular biology techniques such as Western blotting, gene knockout, and gene over-expression.

Moreover, the currently available murine models of MRSA, VRE, and C. albicans infections are limited, making it difficult to fully simulate such clinical infections. This hampers research into the distribution and efficacy of bioactive compounds within infected tissues. There is also a need to improve administrative routes and develop targeted drug delivery strategies. To date, few studies have reported the in vivo pharmacological effects and tissue distribution of these active compounds. Additionally, many plant NPs effective against MRSA, VRE, and C. albicans exhibit poor solubility, permeability, and selectivity. Optimizing and synthesizing new derivatives with enhanced antibacterial efficacy and low toxicity against MDROs is likely to be a key direction for future research.

Currently, the clinical management of MDRO infections often involves combination therapies. Numerous plant-derived NPs have demonstrated strong synergistic effects when paired with existing antibiotics. This strategy of “drug repurposing” not only reduces the risk and cost associated with new drug development but also provides a practical solution to address the escalating issue of MDROs infections, which represents a major breakthrough in overcoming challenges of current antimicrobial drug development. Soon, combinations of plant-derived NPs and antibiotics hold significant potential for clinical translation and market application.

In the future, interdisciplinary collaboration among phytochemists, synthetic chemists, pharmacologists, and artificial intelligence researchers will be essential for the efficient screening, discovery, and development of the next generation of anti-MDRO therapeutics.