In silico discovery of the potential role of Rosmarinus officinalis oil as a natural antibacterial agent for treating infections caused by extended-spectrum beta-lactamase-producing bacteria via molecular docking Weissella: Antimicrobial and Food Biopreservation Potentials
بیوتکنولوژی غذایی کاربردی,
دوره 13 شماره 1 (2026),
7 دسامبر 2025
,
صفحه 1-11(e26)
https://doi.org/10.22037/afb.v13i1.53256
چکیده
- INTRODUCTION
Rosemary is cultivated in almost all regions of the Mediterranean Basin. It is widely used for its therapeutic characteristics [1] because it contains bioactive compounds with several activities, including antibacterial [2], antioxidant, antiparasitic, antifungal and anticarcinogenic activities [3]. Nowadays, antibiotic resistance is a serious public health concern worldwide [4]. According to several researchers, rosemary essential oil (EO) is a potential alternative antimicrobial agent to combat various harmful microorganisms, including Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aeromonas hydrophila, Bacillus cereus, Clostridium perfringens and Salmonella Choleraesuis [5]. The pharmacological effects of EO extracted from this plant are majorly due to its high phenolic component content [6].
Based on the development of antimicrobial resistance in bacterial infections, this investigation assessed the antibacterial efficacy of compounds in Rosmarinus officinalis oil. Thus, it is essential to investigate structurally distinct antibacterial agents with a fewer adverse effects that can eradicate drug-resistant mutations [7]. However, drug investigation is a challenging process, but virtual screening and molecular docking (VS) are the methods in computer-aided drug design (CADD) that have significantly decreased the expenses and lead times connected to medicine development by forecasting the most favorable conformation, position and direction of a small molecule (potential medication) for simplifying further lead optimization. This is the preferred technique [8], when the three-dimensional (3D) structure of the protein target is accessible.
Studies have shown that Gram-negative bacteria are generally more resistant than Gram-positive bacteria [9]. Therefore, the current study focused on a bacterium that best represents antibiotic resistance in Gram-negative bacteria, namely, bacteria that produce extended-spectrum beta-lactamases (ESBLs). The main goal of molecular docking is to design interactions between a target macromolecule (protein) and a small molecule (ligand) [10]. Understanding the precise location and mode of ligand binding facilitates the logical design of modifications to maximize the interactions between proteins and ligands [10].
- MATERIALS AND METHODS
2.1. Strains of Bacteria
Totally, ten Enterobacteriaceae strains were isolated from patients with various infections in various laboratories, Batna, Algeria. Only ESBL-positive bacterial isolates were selected for the characterization of antimicrobial activity. Three strains belonging to the Genus Enterobacter were selected; their molecular identification was carried out at the National Research Center for Antibiotic Resistance, Clermont-Ferrand, France. Thus, the identified species was E. hormaechei hoffmannii.
2.2. Bacterial Culture
MacConkey agar (BioMerieux, France) was used to cultivate strains at 37 °C ±1 for 24 h. The authors screened ESBL production using double-disc synergy test (DDST) with third-generation cephalosporins (cefotaxime, ceftazidime, aztreonam and cefepime) and clavulanic acid [11]. Isolates were identified using biochemical examinations and the identifications were verified using mass spectrometry (MS) with VITEK MS (Bio-Merieux, France).
2.3. The Extraction Process
The plant, R. Officinalis, was collected, stored out of the sun, dried in a temperature-controlled area and then processed into a powder. The extraction process involved steam distillation, as heat caused the plant cells to burst, releasing molecules that creating an azeotropic odor. The distillation process involved immersing the plant raw material (rosemary) in 100 ml of purified water and transferring it over a heat source. The mixture was then heated to boiling. The Gas chromatography-mass spectrometry (GC-MS) method was not carried out. The nine ligands were selected only based on the literature.
2.4. Assessment of Antimicrobial Activity
The antibacterial characteristics of the extract from the extracted oil were assessed against various ESBL-producing bacterial strains of pathogenic enterobacteria using filter paper disk diffusion method (6-mm diameter) [11]. Antibacterial activity was assessed by the presence of an inhibition zone around the disk.
2.5. Molecular Docking
To estimate the affinity between the β-lactamase and the nine components of rosemary EO, molecular docking calculations were carried out using AutoDock Vina [14]. The 3D structure of the β-lactamase target (PDB ID: 5FA7) was achieved from the RCSB protein databank. Ligand structures were modeled and geometry optimized at the optimized and modeled DFT/B3LYP/6-31G(d,p) levels using Gaussian 09 package [15]. Prior to docking, water molecules, except those preserved in the active site and co-crystallized, ligands were removed from the receptors and hydrogen atoms were added. The receptor was treated as rigid, whereas the ligands were considered flexible. Receptor and ligand structures were converted to PDBQT format using AutoDock Tools 1.5.6, the authors treated the ligands as flexible included. the authors removed water molecules (except those in the active site) and all cocrystallized ligands but preserved the hydrogens. The authors removed water molecules (except those in the active site) and all cocrystallized ligands but preserved the hydrogens. The docking search space was defined by a grid box centered at x = -25 y¸= -5 and z = 21 Å, with dimensions of 19 × 19 × 17 Å. The exhaustiveness parameter was set to 50 and a random seed of 2013 was used. Nine docking poses were generated for each ligand and ranked based on the predicted binding affinity calculated using AutoDockTools. The topranked pose was then used for interaction analysis and visualization using Discovery Studio Visualizer [16]. For validation, a re-docking procedure was carried out using co-crystallized ligand 5VR ([[(3R,6S)-6-(acetamidocarbamoyl)-1-methanoyl-piperidin-3-yl]amino] hydrogen sulfate; C₉H₁₆N₄O₇S), extracted from the β-lactamase crystal structure (PDB ID: 5FA7). The ligand was re-docked into a similar binding site using described docking parameters and the resulting top-ranked pose was superimposed on its original crystallographic conformation. The calculated all-atom RMSD between the re-docked and crystallographic poses was 2.29 Å (2.2899 Å), indicating a reasonable reproduction of the crystallographic binding orientation. Avibactam, a known β-lactamase inhibitor, was additionally included as a reference compound for comparaison of the predicted docking scores.
- RESULTS AND DISCUSSION
3.1. The Importance of Protein Choice
Based on the literature, extended-spectrum beta-lactamases (ESBLs) are produced by most Enterobacteriaceae and causing community-acquired and nosocomial illnesses, rendering strains resistant to beta-lactam antibiotics and leading to serious therapeutic failures [17]. The blaCTX-M-type enzymes have become an increasingly serious public health issue. They are spread worldwide and have become the most common ESBLs in human and animal Enterobacteriaceae [18]. Within various blaCTX-M types distributed internationally, blaCTX-M-15 has been reported in humans, animals and the environment. Several studies have identified ESBL-producing genes, in particular, the blaCTX-M-15 variant (CTX-M-1 group), in Algeria, Africa, the USA, Europe, Asia, Canada, France and the UK [19].
3.2. The Importance of Choosing a Ligand
This study aimed to demonstrate an innovative strategy from natural sources such as medicinal plants to eliminate resistant bacterial strains, especially those that produce ESBL enzymes, as a potential substitute for modern medication in treating bacteria that have developed antibiotic resistance [20]. Therefore, it is essential to comprehend how bioactive chemicals are distributed in rosemary EO (ROEO), which is responsible for its antimicrobial effects [21]. The choice of the rosemary plant was based on recent studies, indicating that it includes excellent broad-spectrum antibacterial activity [22].
Rosemary oil contains phenols, alcohols, aldehydes and ketones, which show activity [23]. Within these substances, phenols are the most active substances against bacteria because of the acidic characteristics of their hydroxyl groups [24]. Because alcohols are soluble in aqueous media, they effectively disrupt bacterial cell walls, making them particularly effective against bacterial strains [25]. The antibacterial process of ROEO is majorly due to cytoplasmic membrane disruption, mixed-force kinetics, proton and electron movements, active cellular transport and coagulation of intracellular contents, as well as cell death [26].
3.3. Molecular Docking
The antibacterial activities of EO extracted from R. officinalis and used against ESBL-producing and multidrug-resistant bacteria were assessed. The filter-paper diffusion technique showed that R. officinalis EO demonstrated anti-E. hormaechei Hoffmannii activity, creating a zone of inhibition around the disc impregnated with the extract, ranging from 2 to 4 in diameter. Each strain was assessed three times to provide significant verification of the presence of activity. Based on the absence of GC-MS analysis in the current study, the nine ligands were selected based on their persistence and antibacterial effects in rosemary oil, referring to published scientific literature.
The current molecular docking analysis (Table 1) demonstrated that rosmarinic acid included further favorable predicted docking score/binding affinity under the computational conditions and the highest affinity within the EO components studied for β-lactamase (-8.2 kcal.mol-1). This affinity was ensured by seven hydrogen bonds with active-site residues (Figure 1a). This results were similar to those of several studies, showing that the antibacterial characteristics of rosemary were primarily attributed to rosmarinic acid [27].
Table 1: Binding energy (ΔG) and non-bonded interactions between the nine components of rosemary essential oil and β-lactamase
The current findings also showed that the compounds with the strongest affinity against β-lactamase were carnosol and carnosic acid following rosmarinic acid, with ΔG values of -7.2 and -7.0 kcal.mol-1, respectively. These two components could form relatively stable complexes with the target (Table 1). In general, intramolecular nonbonded interactions between the nine components and the enzyme were either hydrogen bonding, hydrophobic interactions, or the two ones (Figures 1a–1i).
Carnosol and carnosic acid are phenolic compounds in rosemary EO that may include antimicrobial and antioxidant effects [28]. Moreover, the current findings were similar to those of further research [29], demonstrating that rosmarinic acid, carnosol and carnosic acid are the phenolic compounds responsible for the biological activities of R. officinalis and Eucalyptus plants [30], particularly antibacterial activity. Based on the reports, these phenolic acids (rosmarinic acid, carnosic acid and carnosol) include good interactions with bacterial cell wall proteins that are widespread in Gram-positive and Gram-negative bacteria, including penicillin-binding proteins (PBP) and outer membrane protein A (OMPA), which explains the antibacterial characteristics of the selected phenolic acids [31]
It is noteworthy that, in addition to previously highlighted compounds (rosmarinic acid, carnosic acid and carnosol), other compounds included affinity with ESBL enzymes with an almost similar difference in binding energy (ΔG), including β-caryophyllene -5.9 kcal.mol-1, verbenone -5.4 kcal.mol-1 and camphor -5.0 kcal.mol-1. These findings were similar to those of previous research, indicating that caryophyllene [10], verbenone and camphor are antibacterial agents [32], especially against enterobacteria. In addition, the skin readily absorbs camphor, resulting in a cooling sensation similar to menthol [33]. Other components such as 1,8-cineol and α-pinene interacted with the current target with ΔG values of -4.9 and -4.6 kcal.mol-1, respectively. As reported by [34], presence of 1,8-cineol and α-pinene in the EO of rosemary makes it effective against a wide variety of fungal and bacterial infections, especially because α-pinene is the major chemotype in R. officinalis. In addition, several studies have shown that volatile substances (e.g., 1,8-cineol and α-pinene) increases the antibacterial activity of rosmary oil [35].
The current data demonstrated that β-myrcene included the least effective interaction with ESBL (ΔG = -3.9 kcal.mol-1). However, this did not preclude its antibacterial activity, as reported in other studies [36]. The molecular docking results in the current study showed high affinity between microbial proteins (ESBL) and ligands in rosemary EO, particularly rosmarinic acid, carnosol and carnosic acid, which are well known for their bioactivities [37]. Based on the results of the predictions assessed by molecular docking and the current findings, R. officinalis can be recommended in the pharmaceutical sector as a natural antibacterial agent to treat infections caused by clinical or foodborne ESBL-producing isolates [38]. The molecule developed for industrial scale-up must contain the concentrations of each component in rosemary EO, with high levels of rosmarinic acid, carnosol and carnosic acid to ensure sufficient effectiveness against ESBL-producing bacteria.
Based on the results of scientific research worldwide, rosemary EO shows an interactive effect against several strains, including the most common agents that cause hospital-acquired (HA) and community-acquired (CA) diseases, by overcoming and decreasing the impermeability of the membrane. Examples include methicillin-resistant S. aureus (MRSA), E. coli, P. aeruginosa [39], S. epidermidis, Streptococcus sp., Enterococcus faecalis, B. subtilis, A. hydrophila, B. cereus, C. perfringens and Salmonella Choleraesuis [40].
Additionally, earlier published reports [41] have shown that rosemary includes the potential to inhibit several bacteria and may make bacteria further susceptible to common medicines by becoming further active on Gram-positive mutants, compared to Gram-negative mutants. This accurs possibly as a result of the presence of an outer membrane in Gram-negative [42] strains, which restricts hydrophobic chemicals ability to diffuse via its lipopolysaccharide (LPS) cover, as well as inducing its permeability and cell death [43]. The lipophilic ends of Gram-positive bacteria cell membrane contain acids, which facilitate the infiltration of the EO hydrophobic substances [44]. As described by [44] and [45], efflux systems such as the resistance-nodulation-cell division (RND) family are primary sources of resistance and multidrug resistance in Gram-negative bacteria.
- CONCLUSION
The emergence of bacterial resistance to antibiotics leads to therapeutic failure and sometimes death in patients with bacterial infections. These findings have created an urgent need of a natural broad-spectrum antibacterial substance such as rosemary EO, which includes strong medicinal, antibacterial and antioxidant characteristics, as an innovative strategy for eliminating resistant bacterial strains. Therefore, researchers are searching for plant-based substitutes with antibacterial characteristics but with no undesirable side effects of synthetic drugs. Rosemary species include a promising future in healthcare and their therapeutic potentials should be further addressed in food science and human and animal medicines. These findings suggest a promising role for rosemary-derived compounds in addition to conventional antibiotics. Based on the limited number of isolates and the lack of GC-MS characterisation as well as the absence of direct enzyme inhibition assays and quantitative measurements of MIC/MBC, further in vivo investigations are needed to fully clarify their potentials in antibacterial therapy.
- DECLARATION
5.1. Conflict of Interest
The authors declare no conflict of interest.
5.2. Funding
No funding was received for this study.
5.3. Author Contributions With
RA designed the study; RA and ML carried out the experiments; RA and B analyzed the data; RA and HR wrote the manuscript draft; and RA, ML and HR revised the manuscript. All the authors approved the final version of the manuscript.
5.4. Ethical Considerations
All ethical principles were addressed in carrying out and writing this manuscript.
5.5. Data Availability
In accordance with the principles of transparency and open research, the authors declare that all data and materials used in this study are available upon request.
5.6. Using Artificial Intelligence Chatbot
No AI chatbot was used in this study.
- Antibacterial effects, ESBL-producing bacteria, molecular docking, rosmarinic acid, Rosmarinus officinalis
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