UMYU Journal of Microbiology Research

E-ISSN: 2814 – 1822; P-ISSN: 2616 – 0668

REVIEW ARTICLE

Pharmacological Potential of Nigella sativa and Psidium guajava: Bioactive Compounds, Therapeutic Potential, and Challenges in Drug Development

¹Abdulmajid Bashir, ¹MukhtarGambo Lawal and ²Affan Usman

¹Department of Microbiology, Faculty of Natural and Applied Science, Umaru Musa Yar'adua University, Katsina , Nigeria

²Department of Medicine and Surgery, Faculty of Basic Medical Sciences, Umaru Musa Yar'adua University, Katsina , Nigeria

Correspondence author: almajidbish@gmail.com

Abstract

Antimicrobial resistance (AMR) is a growing global health crisis exacerbated by the slow pace of new drug development. This study systematically evaluated the pharmacological and antimicrobial properties of Nigella sativa and Psidium guajava, focusing on their bioactive constituents, clinical relevance, and therapeutic potential. A comprehensive search of nine databases covering the period 2015–2024 yielded 1,057 records, of which 111 full-text articles met the inclusion criteria. Ultimately, 24 studies were included in the qualitative synthesis, and 12 provided quantitative MIC data suitable for meta-analysis. Using a random-effects model, the pooled MIC estimate for thymoquinone was 6.83 μg/mL (95% CI: 4.85–8.82), indicating consistent broad-spectrum antimicrobial activity. Heatmaps and Venn diagrams highlighted compound-pathogen interactions and revealed overlapping and unique antibacterial spectra among thymoquinone, carvacrol, and quercetin-glycosides. The ROBINS-I tool revealed a low to moderate risk of bias in most domains, although the confounding and outcome measurement domains showed a serious risk in a few studies. Notably, publication bias was evident due to selective reporting of favorable MIC values. N. sativa and P. guajava exhibited significant antimicrobial, anti-inflammatory, and antitumor activities, mediated by compounds such as thymoquinone, carvacrol, tannins, and quercetin. These findings emphasize the potential of these plants as adjuncts or alternatives in antimicrobial therapy. However, challenges including standardization, bioavailability, and regulatory frameworks must be addressed through multidisciplinary research and sustainable bioproduction approaches.

Keywords: Nigella sativa, Psidium guajava, antimicrobial resistance, phytochemicals, Bioactive compounds, pharmacological synergy, MIC meta-analysis

INTRODUCTION

Medicinal plants have been an essential component of African traditional medicine frameworks and local health systems across sub-Saharan Africa (Thomford et al., 2015). Plant-derived natural products have played a crucial role in contributing to modern medicine and providing a rich source of bioactive compounds for new drug development (Chaachouay and Zidane, 2024). The renewed interest in this area stems from unmet therapeutic needs, advancements in detection techniques, and improved production methods (Aware et al., 2022).

According to the WHO, 80% of the developing world relies on traditional plant-based medicine (Khan and Ahmed, 2019). Out of an estimated 374,000 plant species, approximately 28,187 have been discovered to possess medicinal properties (Chassagne et al., 2021; Iduh et al., 2024). More than 1,340 of these species exhibit antimicrobial characteristics, and over 30,000 antimicrobial compounds have been isolated (Iduh et al., 2024). Another study estimated that 14-28% of higher plant species are medicinal, and 74% of bioactive plant compounds were discovered through traditional use (Mustafa et al., 2017).

Nigella sativa (black seeds or black cumin) is an annual flowering plant in the Family Ranunculaceae that is native to the Mediterranean region but is also cultivated in Saudi Arabia, northern Africa, and parts of Asia (Al Dhaheri et al., 2022). A great number of investigations and studies were conducted in the past few years, targeting not only the use of these plants but also the testing of their ingredients and active components, which could elucidate or explain these pharmacological actions on both experimental and clinical pharmacology grounds (Shetty et al., 2018; Alobaedi et al., 2017; Memar et al., 2017).

Native to tropical America, Psidium guajava, of the family Myrtaceae, is currently grown worldwide in suitable tropical climates (Proença et al., 2022). This plant has been reported to exhibit excellent antimicrobial activity against several tested strains, which is attributed to its full array of bioactive compounds (Bashir et al., 2021). Recent studies have shown that the bioactive compounds of Psidium guajava possess remarkable antibacterial activity against a wide variety of bacterial pathogens (Bano et al., 2023; Huynh et al., 2025; Díaz-de-Cerio et al., 2017; Bashir et al., 2021). P. guajava contains more than 20 compounds distributed in leaves, stems, bark and roots (Kumar et al., 2021). Guava leaves contain an essential oil rich in cineol, tannins, triterpenes, flavanoids, resin, eugenol, malic acid, fat, cellulose, chlorophyll, mineral salts, and several other fixed substances (Kumar et al., 2021).

Nigella sativa contains various bioactive compounds, of which thymoquinone (TQ) has been the most extensively studied (Mahomoodally et al., 2022). Thymoquinone is a volatile bioactive component recognized for its strong antioxidant, anti-inflammatory, and antimicrobial characteristics (Abbas et al., 2024). It has been demonstrated that it is capable of producing powerful anticancer effects, inducing apoptosis as well as inhibiting tumor growth in several cancer cell lines (Majdalawieh & Fayyad, 2016). Additional compounds of significance include nigellidine, nigellicine, and alpha-hederin, which play a vital role in the immunomodulatory and hepatoprotective abilities of the herb (Fayed, 2022). Besides, other studies have reported the antimicrobial effects of TQ against multidrug-resistant pathogens; hence, TQ is considered a promising target for developing new drugs to overcome antibiotic resistance (Yu et al., 2024). Among these compounds, quercetin was identified as one of the major bioactive phytochemicals in Psidium guajava (Naseer et al., 2018). Quercetin is a well-known flavonoid with potent antioxidant and anti-inflammatory activities and has been linked to cardiovascular protection as well as cancer prevention (Kumar et al., 2021). Moreover, it exhibits antimicrobial effects, especially against resistant bacterial strains (Nguyen and Bhattacharya, 2022).

Although numerous medicinal plants have been explored for their antimicrobial potential, Nigella sativa and Psidium guajava were strategically prioritized in this study due to their extensive ethnopharmacological use (Ugbogu et al., 2022), broad-spectrum antimicrobial activity (Shafodino et al., 2022), and the growing body of scientific evidence supporting their efficacy against clinically relevant drug-resistant pathogens. N. sativa, known for its active compound thymoquinone, and P. guajava, rich in quercetin and tannins, exhibit mechanisms such as membrane disruption, efflux pump inhibition, and reactive oxygen species generation, which are critical in overcoming bacterial resistance (Tiotsop et al., 2023). Unlike many other medicinal plants that lack consistent bioactive profiles, these two species offer reproducible antimicrobial effects and are widely accessible in low- and middle-income countries (Ullah et al., 2020), aligning with WHO's traditional medicine frameworks. Despite their widespread use, previous studies on N. sativa and P. guajava remain fragmented often limited to crude extract evaluations without comparative synthesis or standardized potency assessments (Bylappa et al., 2024; Odieka et al., 2022; Bashir et al., 2021). Moreover, there is a lack of integration between their phytochemical evidence base and the global agenda on antimicrobial resistance (AMR). To address these gaps, this study conducts a systematic review and meta-analysis of minimum inhibitory concentration (MIC) data, applies a rigorous risk-of-bias (ROBINS-I) assessment to the included studies, and contextualizes the findings against WHO-priority bacterial pathogens. By doing so, it provides a consolidated pharmacological profile and a strategic framework for guiding future drug development and policy considerations.

STUDY DESIGN

A modified version of the method described by Chouni and Paul (2018) were adopted where a systematic literature search was conducted using Boolean operators of "Nigella sativa" AND "antimicrobial activity" OR "resistance" OR "MIC", "Psidium guajava" AND "antibacterial" OR "bioactive compound" OR "efflux inhibition", "phytochemical synergy" AND ("plant extract" OR "natural compound") AND "antibiotic". The search was applied to PubMed, Google Scholar, and ScienceDirect, Web of Science, Citationsy, ResearchGate, and LiveDNA and Filters were applied to restrict results to peer-reviewed articles published in English between 2015 and 2024 yielding 1,057 records. After removing 213 duplicates and 42 automatically excluded entries (non-English and non-peer-reviewed), 802 records were screened based on title and abstract. Based on inclusion criteria (reporting MIC or antibacterial outcomes of Nigella sativa or Psidium guajava compounds), 111 full-text articles were evaluated. Of these, 87 studies were excluded for reasons including lack of quantitative MIC data (n = 31), absence of specific plant compounds (n = 21), general pharmacological reviews (n = 10), or studies not involving plant-based antimicrobials (n = 25). The remaining 24 studies met all eligibility criteria and were included in the qualitative synthesis. Among these, 12 studies reported comparable and extractable MIC values suitable for meta-analysis and ROBINS-I risk of bias assessment. The complete selection process is depicted in Figure 1 (PRISMA 2020 Flow Diagram). A meta-analysis was performed using a random-effects model due to the expected heterogeneity in study designs, bacterial strains, and extract types. The primary endpoint was the pooled MIC for each plant compound against clinically relevant bacterial pathogens. MIC data were log-transformed before analysis, and summary statistics were calculated. Studies included in the meta-analysis were limited to those reporting comparable experimental designs and identified test organisms. Heatmaps were generated to visualize pooled antimicrobial effectiveness across compounds and pathogens. Also, a heatmap was constructed to depict the relative sensitivity of key pathogens to various bioactive compounds extracted from Nigella sativa and Psidium guajava. MIC values were color-coded (green indicating high sensitivity and red indicating low sensitivity) and organized by bacterial species and plant compound. This enabled the visualization of compound-specific trends in antimicrobial efficacy and facilitated the identification of high-potential candidates for clinical development.

Figure 1: PRISMA Flow diagram

Chemical Composition of the Nigella sativa Seeds and Psidium guajava

Their multipurpose preventive and relieving effects have been attributed to prominent constituents such as nigellicine, nigellidine, thymoquinone (TQ), dithymoquinone, thymol, and carvacrol (Ahmad et al., 2014). Many other active compounds have also been isolated and identified in different N. sativa varieties. The essential oil of the plant contains various pharmacologically active constituents, such as TQ (30–48%), thymol, thymohydroquinone, dithymoquinone, p-cymene (7–15%), carvacrol (6–12%), sesquiterpene longifolene (1–8%), 4-terpineol (2–7%), t-anethol (1–4%), and α -pinene (Ahmad et al., 2014). The seeds of the plant also contain many nonoily and non-caloric components in trace amounts, including pyrazole alkaloids, isoquinoline alkaloids (nigellicimine and nigellicimine-N-oxide), alpha-hederin (a water-soluble pentacyclic triterpene), saponin (a potential anticancer agent), vitamins (riboflavin, thiamin, niacin, pyridoxine, folic acid, and vitamin E), and minerals (potassium, sodium, calcium, phosphorus, magnesium, copper, and iron) (Gholamnezhad et al., 2016).

On the other hand, guava contains sesquiterpene compounds, including beta-caryophyllene, tans-nerolidol, gloobulol, and D-limonene, with variations among varieties due to genetic variability and other factors (Hassan et al., 2020).

Table 1: Antimicrobial Activity of Nigella sativa Chemical Components

Table 2: Antimicrobial Activity of Psidium guajava Chemical Components

RESULT

Anti-Inflammatory and Immunomodulatory Effect of N. sativa

Nigella sativa has demonstrated significant anti-inflammatory and immunomodulatory properties across various disease models, offering potential therapeutic benefits in diverse conditions. Mushtaq et al. (2024) found that N. sativa seed extract protected against liver injury in a Concanavalin A-induced liver damage model by reducing liver injury markers, such as Alanine Aminotransferase and Aspartate Aminotransferase, as well as oxidative stress levels. Moreover, it modulated pro-inflammatory cytokines and apoptotic pathways, highlighting its hepatoprotective effects. Similarly, Haitamy et al. (2024) demonstrated that N. sativa significantly reduced inflammatory markers, such as Cyclooxygenase-2 (COX-2), p50, and p65, in an Aspergillus niger-induced otitis externa model, showing its potential for treating microbial-induced inflammation. Bashir et al. (2023) highlighted the anti-adipogenic and anti-inflammatory effects of N. sativa in vitro, where the black cumin seed extract inhibited lipid accumulation and reduced the expression of inflammatory cytokines like Tumor Necrosis Factor-alpha(TNF-α) and Interleukin-6 (IL-6) by suppressing Nuclear Factor kappa B(NF-κB) and Mitogen-Activated Protein Kinase (MAPK) pathways. In the context of malaria, Ojueromi et al. (2022) found that N. sativa supplementation in Plasmodium berghei-infected mice reduced parasitemia and modulated inflammatory cytokines, thereby improving antioxidant status and immune function. A similar study by Ojueromi et al. (2024), which used N. sativa -fortified cookies, also revealed a reduction in parasitemia and inflammatory markers, further supporting its potential as a therapeutic agent for malaria-related immune and inflammatory dysfunction. Additionally, Wei et al. (2022) demonstrated that active ingredients from N. sativa activated the NF-κB and MAPK signaling pathways, regulating inflammation and immune responses.

Antitumor Effect of N. sativa

Nigella sativa L. (N. sativa), a plant traditionally used in Middle Eastern medicine, has gained attention for its potential anti-tumor properties, which are attributed to its antioxidant and antiangiogenic effects. Several studies have investigated its therapeutic potential, particularly in cancer treatment. A study by Bahramian et al. (2016) demonstrated that N. sativa crude oil significantly reduced tumor volumes, inhibited angiogenesis (via decreased vascular endothelial growth factor (VEGF) and increased endostatin), and enhanced antioxidant enzyme activities (superoxide dismutase and catalase) in breast tumor-bearing mice. Similarly, Rafati et al. (2019) reported that N. sativa gel alleviated acute radiation dermatitis (ARD) in breast cancer patients undergoing radiotherapy, reducing pain and delaying the onset of severe skin reactions. Moreover, Imaduddin et al. (2022) highlighted the antileukemic effect of N. sativa seed extract in benzene-induced leukemia in rats, showing improvements in blood parameters and demonstrating significant therapeutic efficacy, which is attributed to the presence of bioactive compounds such as alkaloids and flavonoids. Additionally, Aftab et al. (2023) explored the antineoplastic potential of the vegetative part of N. sativa, finding significant cytotoxic effects against the human epithelial cell line (Hep2) and human breast cancer cell lines (MCF7), particularly with n-butanol and chloroform extracts.

Antidiabetic, Antihyperlipidemic, and Hepatoprotective Effects of N. sativa on Metabolic Syndrome

A study by El Rabey et al. (2017) demonstrated that N. sativa methanol extract alleviated biochemical and histopathological alterations in streptozotocin-induced diabetic rats, with effects comparable to those of propolis, although propolis exhibited greater efficacy. Similarly, a pilot study by Pelegrin et al. (2019) found that N. sativa powder did not significantly affect insulin sensitivity or glucose regulation in healthy volunteers; however, it showed potential to lower lipid concentrations, particularly in hyperlipidemic subjects. Moreover, N. sativa has been shown to mitigate oxidative stress and lipid peroxidation in hyperlipidemic rats, improving antioxidant enzyme activities such as superoxide dismutase, catalase, and glutathione-S-transferase (Ahmad & Beg, 2016). Its hepatoprotective effects have also been established in diabetic rats, where it alleviated liver damage by reducing liver enzyme levels and improving histopathological findings (Das, 2016). Furthermore, the effect of N. sativa on vascular health has been highlighted in studies examining endothelial dysfunction in diabetes, where it improved endothelial nitric oxide synthase expression and vasorelaxation in aortic rings, revealing beneficial effects on vascular inflammation (Abbasnezhad et al., 2019). In addition to its antidiabetic, antihyperlipidemic, and hepatoprotective effects, N. sativa oil has been shown to possess genoprotective and free radical scavenging properties, particularly against liver toxicity induced by fungicides (Hashem et al., 2018).

Effects of N. sativa on Neurological, Cardiovascular, and Respiratory Disorders and their Anti-Infertility Properties

A study by Seghatoleslam et al. (2016) showed that pre-treatment with NS hydro-alcoholic extract reduced seizure scores and improved memory and hippocampal histology in rats after pentylenetetrazole-induced seizures. Additionally,Nigella sativa(NS) has exhibited antimanic-like effects and modulated brain inflammatory mediators, with a marked reduction in interleukin-6, tumor necrosis factor-α, and other inflammatory markers (Uzzan et al., 2024). In the context of neurotoxicity, NS oil alleviated aluminum chloride-induced cerebellar damage by reducing nitric oxide metabolites and reactive oxygen species (ROS), and preserving cerebellar histoarchitecture, demonstrating its neuroprotective effects (Imam et al., 2022). Cardiovascularly, N. sativa oil improved vascular function by enhancing flow-mediated dilation and increasing plasma nitric oxide levels, though it had no significant effect on certain adhesion molecules (Emamat et al., 2022). Additionally, NS supplementation improved cardiovascular risk factors in obese and overweight women, increasing high-density lipoprotein (HDL) cholesterol, reducing low-density lipoprotein (LDL) cholesterol, and lowering systolic blood pressure (Razmpoosh et al., 2021). In respiratory health, the addition of NS to standard treatment has improved clinical outcomes in patients with uncomplicated respiratory infections, resulting in faster symptom resolution compared to those receiving standard treatment alone (Elango et al., 2022). Furthermore, in the management of COVID-19, a combination of NS and vitamin D3 enhanced viral clearance and alleviated symptoms more effectively than standard treatment alone (Said et al., 2022). In reproductive health, an ethanolic extract of NS seeds demonstrated hormone-like activities, increasing luteinizing hormone (LH), estrogen (E2), and progesterone levels, and improving fertility in female rats, suggesting its potential for treating female infertility (Nagy et al., 2024).

Anti-Inflammatory and Immunomodulatory Effect of Psidium guajava

A study by Vasconcelos et al. (2017) demonstrated that lycopene-rich extracts (LEG) and purified lycopene (LPG) from red guava exhibited significant anti-inflammatory effects in Swiss mice, as evidenced by reduced paw edema induced by various inflammatory agents, decreased leukocyte migration, and lowered myeloperoxidase (MPO) levels. These effects were associated with the downregulation of inflammatory mediators and an increase in glutathione (GSH) levels. Similarly, Kariawasam et al. (2017) reported that the aqueous leaf extract of Psidium guajava exhibited dose-dependent anti-inflammatory activity, with significant inhibition of egg albumin and bovine serum albumin denaturation. This effect was comparable to the anti-inflammatory drug Diclofenac sodium, and in the egg albumin denaturation assay, guava extract showed nearly 30 times stronger activity. Moreover, studies on the immunomodulatory effects of guava leaves have demonstrated their ability to stimulate both humoral and cell-mediated immunity. Shabbir et al. (2016) found that the methanolic leaf extract of guava significantly increased white blood cell (WBC) count, hemoglobin levels, and platelet counts in mice, while also improving delayed-type hypersensitivity responses and preventing cyclophosphamide-induced myelosuppression. Furthermore, the extract boosted anti-Sheep Red Blood Cell (anti-SRBC) antibody titers and reduced the lethality rate in mice compared to cyclophosphamide treatment, indicating the potential of guava leaves as an immunostimulant.

Antitumor Effect of Psidium guajava

Ashraf et al. (2016) explored the antitumor effects of methanol, hexane, and chloroform extracts of P. guajava leaves on human carcinoma cell lines including human chronic myelogenous leukemia(KBM5), human squamous cell carcinoma(SCC4), andhuman multiple myeloma cell line(U266), revealing dose-dependent decreases in cell viability with IC50 values ranging from 22.73 to 89.55 μg/mL. The hexane extract notably inhibited TNF-α induced NF-κB activation in KBM5 cells, emphasizing its anti-inflammatory potential. Further research by Qin et al. (2017) identified meroterpenoids in guava fruit, specifically psiguajavadial B, which exhibited high cytotoxicity against A549 human lung cancer cells, with an IC50 value of 150 nM. This compound also demonstrated inhibitory activity against topoisomerase I, a crucial enzyme for DNA replication in cancer cells. Meroterpenoids such as Psiguajavadial D and Guapsidial A were shown to exert cytotoxic effects across multiple cell lines, including HL-60 and MCF-7, with IC50 values ranging from 3.21 to 9.94 μmol/L (Kumar et al., 2021). In addition to these compounds, Zhu et al. (2019) isolated guavinoside E, benzophenone, and guavinoside B from P. guajava leaves. Compound 2 showed strong apoptotic activity in HCT116 colon cancer cells through the upregulation of p53 and cleaved caspases. Moreover, Polinati et al. (2022) investigated the effects of lycopene extracted from guava on MCF-7 breast cancer cells, demonstrating its role in inducing apoptosis and modulating the G2-M cell cycle checkpoint.

Antidiabetic, Antihyperlipidemic, and Hepatoprotective Effects of Psidium guajava on Metabolic Syndromes

Psidium guajava, specifically its leaf extracts, has shown promise in managing metabolic disorders, including type 2 diabetes mellitus (T2DM), dyslipidemia, and liver dysfunction. The aqueous extract of guava leaves has been found to improve glucose tolerance, insulin sensitivity, and hepatic glycogen accumulation in diabetic db/db mice, while also restoring gut microbiota composition and increasing GLUT2 expression in hepatocytes (Chu et al., 2022). In streptozotocin-induced diabetic rats, guava leaf extract reduced hormone-sensitive lipase (HSL) activity, increased glycogen storage, and improved lipid profiles by lowering triglycerides, total cholesterol, and LDL cholesterol, while raising HDL cholesterol (Tella et al., 2019). A lycopene-rich extract from red guava fruit has also demonstrated antihyperlipidemic effects by reducing plasma triglycerides, total cholesterol, and LDL cholesterol, along with improving oxidative stress markers in hypercholesterolemic hamsters (Brito et al., 2019). Additionally, Psidium guajava leaf extract has exhibited hepatoprotective effects, mitigating ketoconazole-induced liver damage by reducing elevated alanine aminotransferase (ALT) levels in Wistar rats (Innih et al., 2016).

Antibacterial Activity of Major Compounds in Nigella Sativa against Drug-Resistant Strains

Thymoquinone is a highly effective antibacterial and antibiofilm agent. Goel and Mishra (2018) reported its efficacy against both Gram-positive and Gram-negative bacteria, with MICs ranging from 1.56 to 100 µg/mL. Wang et al. (2022) via disruption of bacterial viability and biofilms while inducing oxidative stress and energy depletion. This compound also proves highly effective against drug-resistant strains, as indicated by Jankowski et al. (2023), who also describe the killing mechanism of Mycobacterium tuberculosis induced by TQ through sigma factor overexpression. Similarly, Dera et al. (2021) highlighted its synergistic effect with antibiotics against pathogens such as Klebsiella pneumoniae and Staphylococcus aureus, emphasizing its role in combination therapies.

Thymol is another notable chemical compound that exhibits strong antibacterial activity and a broader range of applications. Yin et al. 2022 reported its efficacy against drug-resistant Streptococcus iniae and its protective effects in aquaculture. Its property of disturbing cell membranes and homeostasis makes it an effective agent in avoiding food contamination, according to Tian et al. (2021). Farhadi et al. (2024) examined its synergistic effects with antibiotics, such as tetracycline, and emphasized its ability to inhibit biofilms.

A broad-spectrum antibacterial agent, carvacrol synergizes with other components of Nigella sativa, including activity against methicillin-resistant and -susceptible Staphylococcus aureus (Mouwakeh et al., 2019). Wijesundara et al. 2021 and 2022 demonstrated that it damages bacterial cell membranes, inducing increased permeability and a lower cell potential. Mir et al. (2019) Its noteworthiness is especially attributed to its rapid bactericidal activity; however, its modes of action in conjunction with antibiotics render conflicting results, which can only be addressed by careful consideration in terms of therapy.

Table 3: Sensitivity of Multidrug-Resistant Pathogens to Nigella sativa

Antibacterial Activity of Major Compounds in Psidium guajava against Multi-drug Resistant Strains

Psidium guajava has gained significant attention for its antimicrobial properties, particularly against multidrug-resistant (MDR) bacterial strains, including Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. Studies have shown that ethanolic extracts of guava leaves exhibit notable antibacterial activity against carbapenem-resistant K. pneumoniae, with minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) as low as 6.25 mg/ml with the antibacterial activity being attributed to the presence of bioactive compounds such as flavonoids and other antimicrobial phytochemicals (Hackman et al., 2020). Furthermore, guava leaf extracts have demonstrated effectiveness against extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae, which are a major cause of urinary tract infections (Hackman et al., 2020). In addition, guava extracts have been found to possess antibiotic-resistance reversal properties, particularly in P. aeruginosa, where guava bark and leaf extracts resensitize MDR strains overexpressing efflux pumps to commonly prescribed antibiotics, thereby enhancing the efficacy of conventional treatments (Tiotsop et al., 2023). Studies also indicate that guava leaf extracts are effective against other MDR pathogens, including Staphylococcus aureus and Salmonella typhi, with notable antibacterial effects at higher concentrations (Buah et al., 2023; Moses et al., 2019).

Table 4: Sensitivity of Multidrug-Resistant Pathogens to Psidium guajava

Figure 2: Meta-analysis on MIC values

Figure 3: Heatmap of MIC values

Figure 4: Overlap of pathogen sensitivity

Figure 5: Average MIC by Compounds

Figure 6: ROBINS-I Risk of Bias Summary Across Included Studies

A meta-analysis (Figures 2) was conducted on the minimum inhibitory concentration (MIC) values of thymoquinone against three pathogenic organisms reported in independent studies. The pooled MIC estimate using a random-effects model was 6.83 µg/mL with a 95% confidence interval of 4.85 to 8.82 µg/mL, indicating consistent antimicrobial activity across diverse microbial species. Specifically, thymoquinone demonstrated the greatest potency against Staphylococcus aureus (5.00 µg/mL), followed by Penicillium digitatum (7.00 µg/mL) and Colletotrichum gloeosporioides (8.50 µg/mL). The non-overlapping confidence intervals and tight distribution show moderate heterogeneity and robust antimicrobial efficacy. These findings support thymoquinone's broad-spectrum potential, particularly against Gram-positive and fungal pathogens, and emphasize its promise for further preclinical development. The clustered heatmap (Figure 3) depicted the relative antimicrobial potency of six phytocompounds against seven pathogens, based on MIC values (µg/mL). Warmer colors (red and orange) indicate higher MICs (lower potency), while cooler shades (yellow to pale) denote lower MICs and greater efficacy. Notably, carotenoids and thymoquinone clustered together, both exhibiting potent activity across Staphylococcus aureus, Escherichia coli, and Candida albicans, showing a shared spectrum of efficacy. Thymol and quercetin glycosides showed selective activity, with quercetin demonstrating reduced potency against E. coli (high MIC), while carvacrol exhibited narrower, more targeted inhibition against Candida krusei. The dendrograms revealed a degree of overlap in the antimicrobial spectrum among certain phytochemicals, underscoring the potential utility of N. sativa and P. guajava compounds in targeting both Gram-positive bacteria and opportunistic fungi. These visual insights support the prioritization of compounds for future mechanistic studies and antimicrobial formulation development. The Venn diagram (Figure 4) highlighted the overlap in antimicrobial activity among thymoquinone, carvacrol, and quercetin-glycosides based on their target pathogens. Thymoquinone demonstrated the broadest spectrum, uniquely inhibiting two pathogens not shared by the other compounds. Quercetin glycosides and thymoquinone overlapped in their activity against a common pathogen, indicating partial redundancy. Carvacrol showed the narrowest spectrum, targeting a single unique pathogen with no overlap, except for one shared target with quercetin glycosides. These findings showed that while there is some functional redundancy, each compound also contributes uniquely to the antimicrobial portfolio, reinforcing the rationale for multi-compound phytotherapeutic strategies to broaden pathogen coverage. The bar chart (Figure 5) displayed the average MIC values (µg/mL) of six bioactive compounds, highlighting substantial variability in antimicrobial efficacy. Carotenoids and thymoquinone exhibited the lowest average MICs, indicating the highest potency across tested pathogens. Carvacrol and tannins followed with modestly low MIC values, reinforcing their intermediate efficacy profiles. In contrast, quercetin-glycosides showed markedly higher average MIC values, exceeding 2000 µg/mL, indicating comparatively weak antimicrobial activity in vitro. These findings provide quantitative support for the superior potency of compounds derived from Nigella sativa compared to those from Psidium guajava, underscoring their potential for prioritization in further preclinical evaluation and formulation. As illustrated in Figure 6 (ROBINS-I Risk of Bias Summary Across Included Studies), the majority of included studies exhibited low to moderate risk of bias across key methodological domains, particularly in participant selection and intervention classification, indicating overall consistency in inclusion criteria and reporting standards. However, serious risk of bias was identified in critical areas such as confounding due to the absence of comparator groups or failure to control for experimental variables and outcome measurement, where unvalidated or poorly defined MIC reporting undermined reliability. The distribution of reported MIC values shows potential publication bias, characterized by an overrepresentation of favorable outcomes and underreporting of null or weak antimicrobial effects.

DISCUSSION

Multiple mechanisms, including efflux pumps, target modification, and biofilm formation, drive the antimicrobial resistance (AMR) crisis. Phytochemicals present in Nigella sativa and Psidium guajava have shown potential to counteract these mechanisms (Arip et al., 2022). Thymoquinone exhibits membrane-disruptive activity that destabilizes bacterial cell integrity (Wu et al., 2016), while flavonoids, such as quercetin glycosides, have been reported to inhibit efflux pumps (Alnour et al., 2022), thereby increasing the intracellular accumulation of antibiotics. Tannins in P. guajava also impair bacterial adhesion, limiting biofilm development, which is a major contributor to chronic and multidrug-resistant infections (Vermaak, 2020). These multifaceted actions demonstrate that plant-derived compounds not only kill pathogens but may also re-sensitize resistant strains to conventional antibiotics, offering an important strategy for reversing AMR.

The observed synergy between bioactive plant compounds and antibiotics has important therapeutic implications (Vaou et al., 2022). Carvacrol from N. sativa has demonstrated synergy with cefixime and other β-lactams, possibly by enhancing membrane permeability and inhibiting efflux-mediated resistance (Herman and Herman, 2023). This potentiation effect allows for reduced antibiotic dosing, which in turn can minimize side effects and slow the emergence of resistance. Similarly, guava-derived flavonoids have been shown to exhibit additive or synergistic effects in combination with aminoglycosides and tetracyclines (Qu et al., 2019). Such interactions could enable the development of combination therapies that are both cost-effective and clinically viable, particularly in low-resource settings where access to next-generation antibiotics is limited (Chidzwondo and Mutapi, 2024). These findings support the integration of plant-based adjuvants in the design of future antimicrobial protocols.

Despite the promising results, several challenges hinder the clinical application of these plant-derived compounds. First, standardizing plant extracts remains challenging due to variability in phytochemical content across geographical and seasonal contexts (Liebelt et al., 2019). Second, limited bioavailability and stability of compounds like thymoquinone may affect their efficacy in vivo (Hemananthan, 2020). Third, rigorous clinical trials and toxicological assessments are lacking, making regulatory approval difficult (Pognan et al., 2023). Additionally, intellectual property and formulation barriers complicate the incorporation of phytochemicals into mainstream medicine. Addressing these issues requires coordinated efforts in pharmacokinetic modeling, nanocarrier development, and harmonization of herbal pharmacopoeias to enable safe and effective clinical translation (Krishnaswamy, 2024).

CHALLENGES IN THE THERAPEUTICS OF Nigella sativa AND Psidium guajava

The overharvesting of these plant species for their medicinal properties can lead to the depletion of natural resources and pose a threat to the survival of these plant species (Mir et al., 2021). This unsustainable practice raises concerns about ecological balance and biodiversity. Unsustainable plant collection can degrade habitats, disrupt ecosystems, and threaten biodiversity (Kumari et al., 2021). This highlighted the importance of sustainable sourcing methods and the preservation of medicinal plants to protect both ecosystems and the indigenous communities that rely on them. Ensuring consistent quality and effectiveness of plant-based chemicals is difficult because factors such as genetics, environmental conditions, and harvesting practices can alter their chemical composition (Alamgir et al., 2017).

The standardization of plant extracts is significant for consistently replicating their medicinal effects (Govindaraghavan and Sucher, 2015). To ensure the safety and effectiveness of herbal products, it's important to implement stringent quality control measures, including thorough testing and precise quality standards (Heinrich et al., 2022). Variations in bioactive compound concentrations and impurities can impact the reliability and safety of these remedies. The pharmacokinetics of plant-derived substances exhibit significant variability, influencing their bioavailability, distribution, metabolism, and elimination in the body (Chaachouay and Zidane 2022). The efficiency of pharmacological medicines may be influenced by their absorption rates, interactions with other compounds, and chemical stability. Understanding and optimizing the pharmacokinetic properties of plant-derived chemicals is crucial for developing medications that exhibit predictable and consistent therapeutic effects (Stielow et al., 2023).

The development of plant-derived medications involves complex regulatory frameworks that vary by region, requiring rigorous safety and efficacy testing, which can increase costs and timelines (Hossain et al., 2022). Additionally, issues surrounding intellectual property and equitable compensation for indigenous peoples arise from the commercialization of traditional knowledge and plant resources (Bhaduri, 2023). The accessibility and affordability of certain botanical substances, often sourced from specific geographic areas, further complicate their use in clinical settings (Aware et al., 2022). Limited access to plant-based medicines affects underserved communities (Efe et al., 2024). A comprehensive strategy is needed, focusing on conservation, sustainable harvesting, quality control, regulatory alignment, and ethical practices to ensure equitable benefits (Selvakumar et al., 2025). The use of plant-derived chemicals in drug discovery offers substantial potential for innovation in healthcare. However, it is essential to address associated challenges responsibly to maximize benefits while minimizing negative impacts on the environment and society. A balanced approach will ensure sustainable development in this field (Nasim et al., 2022).

PROSPECTS FOR FUTURE RESEARCH

Plant-derived natural compounds remain significant for developing innovative medications and treatments due to their diverse chemical variations (Najmi et al., 2022). This wide array of plant chemicals provides numerous potential applications in medicine, highlighting their ongoing significance in pharmacological research and therapeutic development (Aware et al., 2022). Recent advancements in identifying bioactive substances from plants, combined with a deeper understanding of their mechanisms of action, underscore the feasibility of plant-based drug development (Dar et al., 2023). This approach is increasingly vital as researchers pursue sustainable alternatives in pharmacotherapy (Streicher, 2021). The integration of genomics and metabolomics has played a crucial role in this progress, with the sequencing of plant genomes illuminating the genetic pathways involved in the synthesis of bioactive compounds, thereby enhancing the cultivation and utilization of these valuable resources (Wang et al., 2024). Metabolomics provides a comprehensive analysis of small molecules in plant systems, enabling the precise identification of potential bioactive compounds. Advanced methodologies in this field facilitate functional predictions and genome manipulation to enhance the production of valuable metabolites. This systematic approach streamlines the discovery process, reduces extensive testing, and promotes the development of compounds tailored for targeted therapeutic applications (Zhang et al., 2017).

Biotechnology and synthetic biology play an important role in optimizing the extraction and utilization of plant-derived compounds. Anticipated advancements in bioproduction, genetic engineering, and route optimization are expected to expand the variety of substances obtainable from plants. These innovations aim to enhance both the efficiency and sustainability of producing valuable natural compounds, thus facilitating diverse applications across medicine, agriculture, and industry (Wei et al., 2024). Bioreactors present a sustainable and scalable solution for producing plant-derived molecules, effectively addressing ecological challenges. The incorporation of genetic modifications and pathway engineering allows for the customization of plant metabolites to meet specific pharmaceutical requirements. This approach enhances production efficiency while advancing the development of targeted therapeutics (Upadhyay and Singh, 2023). The future of precision medicine offers significant potential for incorporating plant-derived chemicals into personalized therapeutics. By utilizing genomic and metabolomic data, researchers aim to tailor therapies to match individuals' unique genetic profiles and health conditions. This strategy aims to enhance treatment efficacy and improve patient outcomes through personalized healthcare solutions (Chintada and Golla, 2025). This approach emphasizes the customization of plant-based substances to enhance treatment efficacy and reduce adverse effects. Growing research on the synergy between plant-derived chemicals and traditional medications reveals potential for improved therapeutic outcomes, reduced side effects, and addressing medication resistance in diverse medical conditions (Aware et al., 2022). Future drug development from plant sources will prioritize the exploration of understudied species with medicinal potential. Untapped biological resources worldwide present opportunities for targeted research, potentially leading to the discovery of novel therapeutic compounds and expanding the pharmacological repertoire from natural sources (Chaachouay and Zidane 2024).

CONCLUSION

N. sativa and P. guajava exhibit potent antimicrobial and antitumor activities, yet clinical translation requires standardized extracts, pharmacokinetic studies, and large-scale trials. Future research must prioritize synergistic formulations and sustainable bio-production to combat AMR

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