Phytoconstituents profiling and antimicrobial activity against escherichia coli and staphylococcus aureus of artocarpus heterophyllus extracts: insights from adaptive laboratory evolutionAbstract
The emergence of pathogenic microbes that are resistant to various types of antibiotics and antimicrobial compounds has become a global threat to the global health system and economy. Jackfruit (Artocarpus heterophyllus) leaves are known to have antimicrobial properties. This research was conducted to determine the chemical composition of crude ethanol extracts from A. heterophyllus leaves, antimicrobial activity, and Adaptive Laboratory Evolution (ALE). Antimicrobial activity was tested against Escherichia coli and Staphylococcus aureus. Plant extract’s concentration that were used: 0.1; 0.5; 1.0; 5.0; 10.0; 25.0; and 50.0%. The maximum inhibition zone of A. heterophyllus’s leaves against E. coli and S. aureus was obtained at 50.0% for 6 h. Before ALE, the Minimum Inhibitory Concentration (MIC) for E. coli and S. aureus was 5% at a concentration of 500 μg/mL. Following ALE, on day 15 and day 30, the MIC for E. coli increased to 10%, with effective concentrations of 500 μg/mL on day 15 and 250 μg/mL on day 30. For S. aureus, the MIC after ALE was 10% at 500 μg/mL. In addition, Liquid Chromatography-High-Resolution Mass Spectrometry (LC-HRMS) and Gas Chromatography-Mass Spectrometry (GC-MS) analyses were conducted to determine the phytoconstituents of the leaves extracts. LC-HRMS analysis showed 313 compounds with 3-Dehydrocarnitine dominance. Furthermore, GC-MS analysis revealed 18 compounds, most of which were made up of 9-Octadecenoic acid. The findings of this study suggest that ethanol extracts of A. heterophyllus could be employed as antimicrobial agents.
Keywords:
antimicrobial; ethanol extract; GC-MS; LC-HRMS
Resumo
O surgimento de micróbios patogênicos resistentes a vários tipos de antibióticos e compostos antimicrobianos tornou-se uma ameaça global ao sistema de saúde e à economia global. As folhas de jaca (Artocarpus heterophyllus) são conhecidas por suas propriedades antimicrobianas. Esta pesquisa teve como objetivo determinar a composição química dos extratos etanólicos brutos das folhas de A. heterophyllus, a atividade antimicrobiana e a Evolução Adaptativa em Laboratório (ALE). A atividade antimicrobiana foi testada contra Escherichia coli e Staphylococcus aureus. As concentrações dos extratos vegetais utilizados foram: 0,1; 0,5; 1,0; 5,0; 10,0; 25,0; e 50,0%. A zona de inibição máxima das folhas de A. heterophyllus contra E. coli e S. aureus foi obtida a 50,0% por 6 horas. Antes da ALE, a Concentração Inibitória Mínima (CIM) para E. coli e S. aureus foi de 5%, a uma concentração de 500 μg/mL. Após a ALE, nos dias 15 e 30, a CIM para E. coli aumentou para 10%, com concentrações efetivas de 500 μg/mL no dia 15 e 250 μg/mL no dia 30. Para S. aureus, a CIM após ALE foi de 10% com concentração de 500 μg/mL. Além disso, análises de Cromatografia Líquida-Espectrometria de Massas de Alta Resolução (LC-HRMS) e Cromatografia Gasosa-Espectrometria de Massas (GC-MS) foram conduzidas para determinar os fitoconstituintes dos extratos das folhas. A análise LC-HRMS mostrou 313 compostos com dominância de 3-desidrocarnitina. Além disso, a análise GC-MS revelou 18 compostos, a maioria dos quais constituídos por ácido 9-octadecenoico. Os resultados deste estudo sugerem que extratos etanólicos de A. heterophyllus poderiam ser empregados como agentes antimicrobianos.
Palavras-chave:
antimicrobiano; extrato etanólico; GC-MS; LC-HRMS
1. Introduction
The increasing resistance of microorganisms to various types of antibiotics and antimicrobial compounds has become a global threat to the world's health systems and economies (Abou-Jaoudeh et al., 2024). This resistance causes difficulties in the treatment of infections that were previously easy to treat, as well as worsening the impact of infectious diseases on public health (Okeke et al., 2025). A comprehensive assessment of the global burden of antimicrobial resistance (AMR) has revealed that the two of six leading pathogens responsible for deaths associated with resistance are E. coli and S. aureus (Liu et al., 2025).
E. coli is a major challenge in the medical world, as these Gram-negative bacteria are often the leading cause urinary tract and bile tract infections, which can spread to cause bloodstream infections (BSI) (Stanley et al., 2024). E. coli is the number one causative pathogen, with 829,000 AMR-related deaths (Daneman et al., 2023). The unwise or excessive use of antibiotics in human and animal medicine exacerbates this situation, accelerating the natural selection process that results in more resistant strains of E. coli. Antibiotic resistance in E. coli occurs when these bacteria develop mechanisms that allow them to survive and reproduce despite being exposed to antibiotics (Mokeddem et al., 2025). Meanwhile, S. aureus is a highly pathogenic Gram-positive bacterium and is commonly found on the skin and mucous membranes of humans (Becker, 2018). This bacteria is the most common and damaging pathogen causing musculoskeletal system infections (Hamushan et al., 2024). S. aureus is the third most common cause of foodborne illnesses worldwide, which may survive in raw milk and other food products through intricate processes (Huang et al., 2023). Antibiotic resistance in these bacteria is a significant global health problem (Singh and Kim, 2025).
Microbiological research becomes interested in finding a different treatment to reduce multidrug resistance. These days, novel antimicrobial candidates are investigated in conjunction with specific agents or bioactive substances found in natural goods, such plant extracts. Finding alternate sources of plant-derived antimicrobials, which have long been utilized to treat a variety of illnesses, is one way to deal with this issue (Nametov et al., 2023). Artocarpus heterophyllus commonly known as the jackfruit tree, belongs to the Artocarpus genus and is widely distributed around the world, particularly throughout South and Southeast Asia (Mursyidin and Setiawan, 2023). A. heterophyllus being known as a food source rich in nutrients, also have great potential as medicinal plants because the content of active compounds in various parts of the plant, such as leaves, fruits, and roots, which have been shown to have antiproliferative and anti-inflammatory ( Liu et al., 2020), antioxidant effects (Li et al., 2021), and antimicrobial (Hudaya et al., 2024).
Plant extracts containing bioactive compounds can be used in adaptive laboratory evolution (ALE) to accelerate the selection process of microorganisms that are more resistant to certain environmental conditions, thus opening up new potential in the development of microbial strains with optimal capabilities for drug or biopharmaceutical production. Additionally, ALE is essential for researching the mechanisms underlying antibiotic resistance (Tirloni et al., 2023). Through the evolution of microbes exposed to different antibiotics and plant extract, it can find new mutations that confer resistance and comprehend the intricate relationship between genotype and phenotype in the development of bacterial resistances (Hartono et al., 2023). This method used to develop microorganisms that have certain traits through gradual selection in the laboratory. In the context of antimicrobial testing, ALE can be used to develop microbial strains that are more resistant to specific antimicrobial treatments or substances.
Many studies have conducted antimicrobial testing using plant extracts, but few have integrated this with ALE approaches. This research aims to combine both methods by investigating how microbes adapt to selective pressures exerted by ethanol extracts of A. heterophyllus leaves, and how microbes respond to the natural antimicrobial compounds present in these extracts. By linking ALE with antimicrobial assays, it becomes possible to evaluate how microbes that have undergone adaptive evolution in the presence of jackfruit leaf ethanol extract alter their resistance or susceptibility to the extract’s bioactive compounds. For example, during the ALE process, microbes that have grow may exhibit increased resistance to the active components in plant extracts, providing deeper insights into the mechanisms of microbial resistance to natural antibacterial and the potential development of plant extract-based therapies. As such, ALE can provide a deeper understanding of how microbes interact with antimicrobial compounds and how their effectiveness can be maintained or improved.
2. Materials and Methods
A. heterophyllus leaves were collected from the Universitas Airlangga, Surabaya, Indonesia in January 2024. The air-dried A. heterophyllus leaves were extracted at room temperature with 96% ethanol (100 g of plant material in 500 mL of ethanol for each extraction). The final ethanol extract was filtered using a filter paper (Whatman No. 1) and evaporated at 40 °C using a rotary vacuum evaporator. Five hundred grams of A. heterophyllus leaf powder was macerated with 3 L ethanol for 24 hours at room temperature. The maceration process was repeated three times. The ethanol extract was then diluted in Dimethyl sulfoxide (DMSO) to obtain extract concentration of 10, 25, 50 and 100 µg/mL for anti-microbial-assay. The antimicrobial activity index (AI) is a quantitative measure that compares the antimicrobial effectiveness of a compound against a standard reference. AI is a measurement of how effective a substance to stop the growth of microorganisms. It can be used to compare the efficacy of different substances or extracts. It is often derived from the inhibition zone diameter in diffusion assays or calculated based on MIC values. The AI provides insights into the relative potency of different antimicrobial agents against specific pathogens. To evaluate the antibacterial activity of the crude extract, the Kirby-Bauer disc infusion assay was employed following the protocol adapted from (Zouaghi et al., 2021). All antimicrobial assays were performed in three independent replicates, each starting from freshly prepared microbial cultures and extract solutions. Briefly, cultures with an OD600 of 0.8, were inoculated into medium solutions for each treatment in triplicates. Bacterial cultures were incubated at 37°C for 24 h, with agitation at 100 r/min. That standardized bacterial broth culture was streaked evenly on sterile Muller Hinton Agar (MHA, Oxoid) plates. Sterile paper discs (Oxoid) saturated with 100 µL of each extract concentration (0.1; 0.5; 1.0; 5.0; 10.0; 25.0; and 50.0%) were placed on the plates and incubated for 24h at 37°C. For comparison, chloramphenicol-(C)30µg, kanamycin(K)30µg, and tetracyclin(TE)30µg (Oxoid) were used as a positive control. Three replicates were made for each of the bacterial isolates. Finally, the plates were incubated at 37°C whereby the antibacterial activities were measured by calculating the inhibition zone diameter around paper disc for 24 h. The Formula 1 for calculating the AI is:
Ztest = The zone of inhibition (in mm) caused by plant extract.
Zcontrol = The zone of inhibition (in mm) caused by antibiotic.
AI = 1: The antimicrobial activity of the test sample is equal to that of the control (standard antimicrobial agent).
AI > 1: The test sample has higher antimicrobial activity than the control.
AI < 1: The test sample has lower antimicrobial activity than the control.
Minimum inhibitory concentration (MIC) is defined as the lowest sample concentration that completely inhibits the growth of microbes. The MICs of the plant’s extract in a series of concentrations were tested in Mueller Hinton Broth (MHB, Oxoid) for 24h at 37°C. ALE conducted by 30x transfer in media supplemented with ¼ MIC extract (37°C with agitation at 100 r/min). Thirty times transfer conducted by the bacterial culture is serially transferred 30 times. Each transfer involves moving a small portion of the culture into fresh growth medium to allow continued growth and adaptation over multiple generations. Media supplemented with ¼ MIC extract based on the growth medium used for each transfer contains the plant extract at one-quarter of the MIC. Using ¼ MIC applies a sub-inhibitory selective pressure, allowing microbes to grow but encouraging adaptation to the antimicrobial compounds. In summary, the ALE protocol involves repeatedly culturing microbes 30 times in fresh medium containing a sub-lethal concentration (¼ MIC) of the plant ethanol extract. This approach selects for microbial populations that adapt over time to the presence of the extract, enabling study of evolutionary changes in resistance or susceptibility. Moreover, MIC test were conducted after 15th and 30th transfer.
For a comprehensive profiling of the plant extract’s compounds, Gas Chromatography-Mass Spectrometry (GC-MS) and Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) analyses were employed, providing a detailed chemical and biological characterization. GCMS is ideal for smaller, volatile compounds, whereas LC-HRMS is more versatile and can handle complex, non-volatile, or large molecules, making it more suitable for biomolecular and clinical applications The plant extract samples were analyzed at Integrated Research and Testing Laboratory Universitas Gadjah Mada to GC-MS analysis was performed using QP2010M (Shimadzu, Japan). The chemical components were identified by mass spectral analysis of the GC peaks by using the National Institute of Standards and Technology (NIST) and Wiley library. LC-HRMS using Orbitrap LC-HRMS (Thermo scientific) in Corpora Science is an essential instrument for precise analysis of complex mixtures, to conduct thorough studies of molecular structure, concentration, and composition in various fields.
3. Result and Discussion
The activity index of antimicrobials serves as an essential tool for evaluating their effectiveness against various microorganisms. The index of inhibitory activity against E.coli in jackfruit extract using the disc diffusion method is shown in Figure 1. Figure 1 is based on the average activity index calculation of various concentrations of extracts against different types of antibiotics (C30, K30, TE30). Chloramphenicol, kanamycin, and tetracycline are three important antibiotics used to treat various bacterial infections. Each antibiotic has unique properties and mechanisms of action. Based on Figure 1, the most optimal inhibition recorded at the concentration of 50% (K30) at the 6th hour, which is 26.84. The index of inhibitory activity against S. aureus in A. heterophyllus extract using the disc diffusion method is shown in Figure 2. Based on Figure 2, the most optimal inhibition was recorded at the concentration of 50% (K30) at the 6th hour, which is 48.78.
Antimicrobial activity index of various concentrations of A. heterophyllus extract against E.coli.
Antimicrobial activity index of various concentrations of A. heterophyllus extract against S. aureus.
A high AI indicates strong antibacterial properties, which can be particularly valuable in combating multidrug-resistant (MDR) bacteria. The AI of plant extracts can be higher than that of synthetic antibiotics for several reasons related to the unique properties of plant compounds and their mechanisms of action. Crude plant extracts often demonstrate greater antibacterial effectiveness than purified compounds due to the presence of multiple bioactive molecules that can act synergistically. This synergy means that the combined action of various phytochemicals in the crude extract enhances antimicrobial activity more than any single isolated compound alone (Kebede and Shibeshi, 2022). These compounds may act on multiple bacterial targets at once, offering synergistic effects. The AI of plant extracts can be higher due to the complexity and diversity of their chemical composition, which leads to synergistic effects, multiple mechanisms of action, and broad-spectrum activity. This makes them more effective in some cases, particularly against resistant microorganisms, and provides an advantage over single-compound antibiotics. Additionally, their lower tendency to induce resistance, combined with their potential for use in combination with other treatments, contributes to their higher antimicrobial efficacy in various contexts (Mehta, et al. 2021) .
The index of inhibitory activity of A. heterophyllus extract against S. aureus higher than E.coli (Figure 1 and 2). This result in line with another study that E.coli is the most antibiotics resistant isolates (Soliman et al., 2024). E. coli’s higher genetic diversity, outer membrane structure (Wan et al., 2024), ability to acquire resistance genes from various sources presence of efflux pumps, and greater exposure to antibiotics in the environment (Checcucci et al., 2024) contribute to its increased resistance compared to S. aureus. The biological characteristics of E. coli allow it to develop and spread resistance more efficiently than S. aureus. In E. coli, antibiotic resistance can occur through several mechanisms, including genetic mutations, transfer of resistance genes between bacteria via plasmids, or changes in the bacterial structure that block antibiotic penetration. Antibiotic-resistant strains of E. coli become more difficult to treat, which can lead to longer treatment, increased healthcare costs and higher mortality rates (Leopold et al., 2024).
Based on the results of MIC E. coli, the optimal concentration of A. heterophyllus extract to inhibit the growth of E. coli was 5% with a concentration of 500 μg/mL, while MIC S. aureus at the optimal concentration of A. heterophyllus extract to inhibit the growth of S. aureus was 5% with a concentration of 500 μg/mL. ALE, a process in which bacteria are subjected to A. heterophyllus extract with over an extended period. The goal is to observe how these bacteria evolve, typically developing resistance mechanisms to the selective pressures. The MIC after ALE is an important marker for understanding how bacteria adapt to selective pressures. As bacteria evolve during ALE, they may develop resistance, resulting in an increase in MIC. This process underscores the challenges faced in combating antibiotic resistance and highlights the importance of monitoring MIC changes to assess the effectiveness of treatment strategies in the long term. Bacteria strain (E. coli and S. aureus) to test with a low concentration of A. heterophyllus extract over multiple generations. Initially, the MIC of A. heterophyllus extract might be low, but as the bacterial population is exposed to the plant extract over time, some bacteria will survive due to spontaneous mutations or genetic changes. These bacteria may develop resistance mechanisms that help them tolerate higher concentrations of plant extract (Harwani et al., 2022).
Based on the results of MIC E.coli before and after ALE (Figure 3), it has an optimal concentration of A. heterophyllus extract to inhibit the growth of different E.coli. The MIC of E.coli before ALE was 5% with a concentration of 500 μg/mL while the MIC of E.coli after ALE on the 15th and 30th day was the same at 10% with concentrations of 500 μg/mL and 250 μg/mL, respectively. After several generations of this selective pressure, the MIC of plant extract for the E. coli strain might rise significantly. This means that the bacteria have adapted to the plant extract, and a higher concentration is now required to inhibit their growth. Previous study indicated that E. coli strain combined exposure to 1–500 mg/L d-p-hydroxyphenylglycine (DHPG) and 1 mg/L ampicillin (AMP) synergistically increased the mutation frequencies again multiple antibiotics by up to 2928.9-fold in a dose–time pattern, and the combination index (CI) reached 445.7. The CI is a quantitative measure used in antimicrobial assays to evaluate the interaction between two or more antimicrobial agents when used in combination. It helps determine whether the combined effect of the agents is synergistic, additive, or antagonistic. Phenotypic and genotypic analyses revealed that the synergism between DHPG and AMP was associated with increased antibacterial activity, enhanced oxidative stress, and stimulation of efflux pump expression. Overall, our results highlight the elevated risk of antibiotic resistance (AR) induction caused by antibiotics and organic pollutants (Miao et al., 2025). Over time, through mutation and selection, the bacteria might develop resistance mechanisms, such as modifying their cell wall, increasing efflux pump activity, or acquiring resistance genes (Saci et al., 2024). Adaptive resistance evolution is driven by the interplay of transition mutations that introduce genetic variation, positive natural selection that favors resistant variants, and the horizontal gene flow of extended-spectrum β-lactamase (ESBL) genes that disseminate resistance traits across Gram-negative bacterial populations (Popoola et al., 2024).
Figure 4 showed the results of MIC S.aureus before and after the ALE, it has an optimal concentration of A. heterophyllus extract to inhibit the growth of different S.aureus. The MIC of S.aureus before ALE is 5% with a concentration of 500 μg/mL while the MIC of S.aureus after ALE on day 15 and day 30 is the same, as 10% with a concentration of 500 μg/mL. During ALE, bacteria are continuously exposed to sublethal concentrations of plant extract, forcing them to adapt. Mutations occurring at different positions within the mprF gene are widely acknowledged as key factors driving antibiotic resistance in S. aureus strains after ALE. Moreover, resistant strains had a less perturbed proteome profile upon antibiotic challenge as it only needed to activate certain resistance-associated mechanisms (Sulaiman et al., 2021) As a result of these adaptations, the MIC for the bacteria increases. This means that the concentration of antibiotic required to inhibit growth of the bacteria becomes higher after ALE, indicating an increase in resistance
Figure 5 and Table 1 depict GCMS analysis of A. heterophyllus extract. The 9-Octadecenoic acid commonly known as oleic acid dominance. This compound also detected in other plant extract i.e. Plumbago zeylanica L., Limonia acidissima L. Artocarpus heterophyllus Lam (Krishnan et al. 2017), Pergularia daemia (Alghamdi et al., 2021), Dioscorea communis (Tsami et al., 2022), and Boehmeria nivea (Wulandari et al., 2024). Oleic acid has promising antibacterial properties due to its ability to disrupt bacterial cell membranes, inhibit biofilm formation, and induce oxidative stress (Ghareeb et al., 2022). Its natural origin and ability to enhance the efficacy of conventional antibiotics make it a potential candidate for addressing bacterial infections, particularly in the context of antibiotic resistance. Another study indicated that leaf and shoot extracts of Ricinus communis showed antibiotic activity against E.coli isolated from apple juice (Shahzad et al., 2024). Numerous phytochemical substances, including catechins, triterpenes, tannins, alkaloids, flavonoids, amino acids, cardiac glycosides, anthocyanidins, reducing sugars, and saponins, are present in ethanolic extracts (Pinoargote-Chang et al., 2025).
Figure 6 indicated 313 compound was detected in A. heterophyllus extract by LCHRMS analysis. Table 2 provided the chemical compound dominance is 3-Dehydrocarnitine. This compound as terminal metabolite of S. aureus biofilm (Zhang et al., 2021). There is no evidence to suggest that 3-dehydrocarnitine possesses antimicrobial activity or structural features that contribute to such activity. Instead, 3-dehydrocarnitine functions as an intermediate in the carnitine degradation pathways of bacteria (Piskol et al., 2024). Erucamide has been identified as a compound with notable antibacterial properties. It has shown activity against a variety of bacterial strains, including both Gram-positive and Gram-negative bacteria (Xie et al., 2021). DL-Stachydrine demonstrates significant antibacterial activity against a range of pathogens through mechanisms such as osmoprotection and potential inhibition of virulence factors (He et al., 2024).
4. Conclusion
This study demonstrates the potential of A. heterophyllus leaves extract as an effective antimicrobial agent against E.coli and S. aureus. The extract exhibited antibacterial activity, showing promise as an alternative or adjunct to conventional antibiotics against these pathogenic bacteria. Additionally, the ALE process revealed the dynamic nature of bacterial resistance mechanisms. After prolonged exposure to the extract, the MIC values of both E. coli and S. aureus increased, highlighting the potential for bacteria to adapt and develop resistance over time. This finding underscores the need for continuous monitoring of resistance patterns and suggests that combining plant-based antimicrobial agents like A. heterophyllus leaves extract with other strategies could help mitigate resistance development. The study also opens avenues for further research into optimizing the use of plant extracts in combating multidrug-resistant bacterial infections, offering valuable insights into the integration of natural products in modern antimicrobial therapy.
Acknowledgements
This study was funded by Riset Kolaborasi Indonesia (RKI) 2024 scheme between Universitas Negeri Yogyakarta (T/18.1.14/UN34.9/PT.01.03/2024), Universitas Airlangga (725/B/UN3.LPPM/PT.01.03/2024), and Institut Teknologi Bandung (91/IT1.B07.1/SPP-LPPM/IV/2024). The authors greatly acknowledged Universitas Negeri Yogyakarta for the support of this study. The authors would like to thank Nadiya, Fatimah, and Syantriadji for the technical assistance in this study.
Data Availability Statement
The research data are only available upon request to the corresponding author.
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Editor:
Ana Paula Peron
