Chalcones as a Strategy against Bacterial Resistance: Structural Modifications and Mechanisms of Action in the Last Decade

Rising resistance to conventional antifungal agents, along with concerns over toxicity and environmental safety, has intensified the search for more sustainable and safer alternatives. Natural oils, particularly essential oils and certain fixed oils, have drawn attention for their broad-spectrum antifungal properties and favourable safety profiles. This review aims to provide a comprehensive overview of the antifungal potential of natural oils, exploring their mechanisms of action, practical applications, and recent advances in formulation strategies. To ensure transparency and reproducibility, this review followed a systematic literature search strategy covering peer-reviewed studies published between 2021 and 2025. The selection focused on research exploring the chemistry, biological activity, and translational applications of natural oils with antifungal potential. Eligible studies were critically analyzed, and findings were narratively synthesized to identify key trends and evidence gaps. Particular emphasis was placed on understanding the effects of these oils on fungal cell structures and functions, as well as their potential applications in healthcare, agriculture, and food preservation. Natural oils exhibit multiple mechanisms of antifungal action, including disruption of fungal cell membranes and walls, inhibition of biofilm formation, interference with virulence factors, and modulation of cellular processes like efflux pump activity and mitochondrial function. The use of natural oils extends across topical medical treatments, crop protection, food preservation, and industrial systems. Innovations in nanotechnology and synergistic formulations have further enhanced their efficacy. However, challenges remain in standardization, stability, and delivery optimization, including limited clinical trials demonstrating real-world efficacy against resistant strains like Candida albicans biofilms. Natural oils hold significant promise as effective antifungal agents within integrated approaches to human health, agriculture, and food safety. Continued research and technological innovation are essential to fully harness their potential and address current limitations in formulation and application, such as regulatory hurdles in clinical translation.

Ellagic acid screened from Rosa rugosa cv. 'Plena': Antibacterial mechanism against Staphylococcus aureus and application in leafy vegetable preservation.

Malaria is a parasitic infection which affects approximately 300 million people worldwide causing over one million deaths each year. There are few diseases that have the same impact on human social and economic development than malaria. In areas where malaria is prevalent, the disease can account for up to 40% of public health expenditure and 50% of all hospital visits. It is clear that in order to relieve the burden of malaria novel, cheap, effective treatments need to be investigated, as in this project. In order to suppress the resistance of the disease to drugs, antimalarials with novel mechanisms of action need to be developed. In this research project, plasmodia1 tubulin has been investigated as a potential drug target. Microtubules play several critically important roles throughout the entire parasite life cycle. Most notably, they form the mitotic spindle during cell division and even a slight disruption of the microtubule dynamics can have a severe impact on the viability of the parasites Although tubulin is present in all eukaryotic cells, it may be sufficiently different from organism to organism to engage in selective targeting. Known antitubulin compounds, including current anticancer drugs such as paclitaxel, do not have selectivity to discriminate between parasite and human tubulin. Although most of the microtubule inhibitors studied to date are equally effective at poisoning parasite and human cells, two distinct classes of common herbicides, the dinitroanilines and the phosphorothioamidates, are potentially selective. The lead compounds for this project, amiprophosmethyl and butamifos, are off patent herbicides that have been tested for their anti-malarial activity Analogues of amiprophosmethyl, an antitubulin compound that appear to exhibit selective antitubulin activity, were designed with diverse architectures around the pentavalent phosphorus atom and many of these compounds have been synthesised and characterised. These modifications include: variations of substituents on the aromatic ring, replacement of the aromatic ring with other cycles, extension and branching of the amino chain, synthesis of cyclic ox-aza analogues, cyclic oxobenzodioxaphosphininylamines, thiophosphoryl and phosphoryl analogues, a series of hybrid molecules incorporating known antimalarial pharmacophores such as quinolines and chloroquinolines. A library of 97 compounds was successfully synthesised based on several modifications of the lead structures. These compounds were tested against several parasite species and the results analysed in terms of their Structure Activity Relationships. When tested against leishmania and trypanosomes, the test compounds were not more active than standard reference therapies. However, several of the compounds showed interesting activity against plasmodia, with 6 showing higher biological activity than the lead compounds. Of these the hybrid drugs combining a chloroquine pharmacophore along with an organophosphate pharmacophore induced and improvement in activity over that observed with either drug component seperatly.

Nosocomial infections caused by microbial opportunistic infections or microbial biofilms may occur during hospitalization and increase patient morbidity, mortality and health care costs. Artificial antibiotic agents were initially used to prevent infection; however, the high prevalence of nosocomial infections has resulted in their excessive use, which has led to microbial resistance to these agents. The increase in microbial resistance to antibiotics and the development of antibiotic agents may be the cause of the production of other microbial resistance. Thus, natural compounds that have no adverse side effects would be a preferred treatment modality. Recently, the monosaccharide 1,5-anhydro-D-fructose (1,5-AF), a natural plant compound derived from starch, has been found to have multifunctional properties, including antioxidant, antiplatelet aggregation by thrombin and anti-inflammatory activities. The results of the present study demonstrate that 1,5-AF suppressed the growth of coagulase-negative staphylococci on the hands as well as the growth of Staphylococcus epidermidis, which is a cause of opportunistic infections. Furthermore, 1,5-AF suppressed biofilm formation by the methicillin-resistant Staphylococcus aureus. In conclusion, 1,5-AF is a natural compound that may be effective in preventing nosocomial infections, without causing adverse side effects.

Quinoline Hydrazide/Hydrazone Derivatives: Recent Insights on Antibacterial Activity and Mechanism of Action.

Dehydroeffusol (DHE) is a natural phenanthrene compound derived from Juncus effusus L., traditionally used for its antimicrobial properties. Despite its historical use, its antibacterial efficacy and underlying mechanisms have not been fully explored. To evaluate the antibacterial activity, safety profile, and mechanism of action of DHE against Staphylococcus aureus (S. aureus), including methicillin-resistant S. aureus (MRSA), and to assess its potential as a therapeutic agent. DHE was isolated and its antibacterial effects were assessed using broth microdilution, time-kill assays, and biofilm inhibition assays. The cytotoxicity and hemolytic activity of DHE were evaluated in vitro using several cell lines and red blood cells. Mechanistic studies included scanning electron microscopy, membrane potential and permeability assays, network pharmacology analysis, molecular docking, and untargeted metabolomic profiling. DHE exhibited appreciable bactericidal activity against S. aureus and MRSA with minimal cytotoxicity. It inhibited biofilm formation, disrupted bacterial membranes, and maintained bactericidal activity without rapid resistance, while synergizing with ciprofloxacin, streptomycin, and azithromycin. Network pharmacology and docking identified 56 infection-related targets (hub proteins EGFR, BCL2, HSP90AA1/B1, ESR1, SRC) enriched in PI3K-Akt/ErbB/EGFR pathways, supporting additional modulation of host infection-related signaling. In MRSA, untargeted metabolomics showed broad disturbances in amino acid, energy, and nucleotide metabolism, indicating disruption of essential biosynthetic and energy pathways. In vivo, DHE significantly reduced bacterial load and alleviated tissue damage in a murine MRSA infection model, demonstrating measurable protective effects. DHE is a promising natural antimicrobial agent with notable activity against S. aureus and MRSA. Its mechanism of action involves membrane disruption and biofilm inhibition, along with preliminary safety in vitro, supporting its potential for further development as an effective antimicrobial agent.

Bicyclic polyprenylated acylphloroglucinols and their derivatives: structural modification, structure-activity relationship, biological activity and mechanism of action.

Today, the phenomenon of multi-drug resistance has become a major cause of concern, and insufficient achievements have been made in the development of new antibiotics for the treatment of bacterial infections. Therefore, there is an unmet need for new auxiliary search. Vitamin C is one such promising supplement. The current study was conducted with the aim of explaining the antibacterial interaction effect of vitamin C in different concentrations (5-20 mg/ml) and drugs effective on Escherichia coli bacteria. In order to collect clinical samples during the months of September to November 2022, clinical samples were collected from 100 patients suspected of urinary tract infection who referred to medical centers. For identification, biochemical tests and gram staining and culture in IMViC and EMB environments were used to see metallic green polish. Then antimicrobial sensitivity test And the effect of antibiotic on biofilm formation, the effect of antibiotic and ascorbic acid on biofilm formation, biofilm inhibition rate was done for the single and combined effects of both antimicrobial substances. Finally, in order to investigate and identify the virulence gene of the isolated strains, DNA extraction was performed by PCR method. 45 samples of urinary infection culture were identified from the total of 100 samples collected, in 45 (45%) of them colonies with metallic polish were observed. 45% were men and 55% were women, and of these, a total of 45 positive E. coli cases were found in women and 17 positive cases were seen in men. Less than one year, teenagers, young and old were divided. 2 cases (2%) were in the age group of less than one year, 3 cases (3%) were teenagers, 63 cases (63%) were young and 32 cases (32%) were in the age group of middle-aged people. In a situation where the ability to form biofilm under vitamin C (ascorbic acid) treatment was not very effective and did not differ much from normal conditions, antibiotic treatment (under MBC gentamicin treatment) was somewhat successful in inhibiting biofilm formation, finally with the combination of antibiotic and Ascorbic acid was completely isolated in many resistant strains, the inability to form biofilm was evident, and this indicated the synergistic effects in the investigated composition. As the results showed, the ability to produce biofilm in the samples that had the target genes in this study was not much different from the other samples. Considering the increasing resistance to some antibiotics and wide changes in the effective spectrum of drugs and preventing the increase of drug-resistant cases, the necessity of conducting drug sensitivity tests seems very necessary. The high prevalence of E. coli antibiotic resistance and the high percentage of resistance genes in patients suffering from infections caused by this bacterium can indicate the excessive use of antibiotics. Finally, the prevalence of antibiotic resistance is a useful marker for investigating resistance genes and can be useful in ecological investigations. Also, with clear inhibitory effects, the selected antibiotic in this study along with ascorbic acid, this vitamin can be used as a supplement in some infections caused by E. coli bacteria.

The rapidly increasing rate of antibiotic resistance is of great concern. Approximately two million deaths result annually from bacterial infections worldwide. Therefore, there is a paramount requirement to develop innovative and novel antibacterial agents with new mechanisms of action and activity against resistant bacterial strains. For this purpose, a set of benzothiazole and N-phenylpyrrolamides derivatives reported as DNA Gyrase B (GyrB) inhibitors were collected from the literature and docked inside the receptor cavity of DNA Gyrase B (PDB ID: 5L3J). The best 10 docked complexes were used to identify novel antibacterial chemical agents through a de novo design approach. Out of initial 300 chemical analogues, the best six analogues were identified using screening with a set of criteria followed by pharmacokinetic analysis. The binding interactions of the best six analogues revealed that all molecules formed a number of critical interactions with catalytic amino residues of DNA Gyrase B with high binding energy. The predicted inhibitory constant biological activity based on binding energy supported the potential of the molecules as DNA Gyrase B ligands. The RMSD, RMSF, and radius of gyration parameters obtained from the 100 ns molecular dynamics simulation study clearly demonstrated that all six analogues were efficient enough to form stable complexes with DNA Gyrase B. High negative binding energy of all ligands obtained from MM-GBSA approach undoubtedly explained the strong affinity toward the DNA Gyrase B. Therefore, the proposed de novo designed molecules can be considered as promising antibacterial chemical agents subject to experimental validation, in vitro.Communicated by Ramaswamy H. Sarma

Antimicrobial peptides: has their time arrived?

Natural products are an invaluable source for the discovery of drug and pesticide candidates. Piperine, a simple and pungent alkaloid, is isolated from several plants of Piperaceae. Piperine and its derivatives displayed a wide range of biological properties, such as antitumor activity, anti-inflammatory activity, antioxidant activity, neuroprotective activity, insecticidal activity, etc. In recent years, lots of works focused on the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been conducted. To the best of our knowledge, however, few review articles related to the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been reported to date. Therefore, this review summarizes the research advances (from 2014 to 2020) of piperine and its derivatives regarding bioactivity, mechanisms of action, total synthesis, and structural modifications. Meanwhile, the structure-activity relationships of piperine and its derivatives are also discussed.

The aim of this study was to assess the efficacy of four natural antimicrobial compounds (cinnamaldehyde, eugenol, resveratrol and thymoquinone) plus a control chemical disinfectant (sodium hypochlorite) in inhibiting biofilm formation by Listeria monocytogenes CMCC54004 (Lm 54004) at a minimum inhibitory concentration (MIC) and sub-MICs. Crystal violet staining assay and microscopic examination were employed to investigate anti-biofilm effects of the evaluated compounds, and a real-time PCR assay was used to investigate the expression of critical genes by Lm 54004 biofilm. The results showed that five antimicrobial compounds inhibited Lm 54004 biofilm formation in a dose dependent way. Specifically, cinnamaldehyde and resveratrol showed better anti-biofilm effects at 1/4 × MIC, while sodium hypochlorite exhibited the lowest inhibitory rates. A swimming assay confirmed that natural compounds at sub-MICs suppressed Lm 54004 motility to a low degree. Supporting these findings, expression analysis showed that all four natural compounds at 1/4 × MIC significantly down-regulated quorum sensing genes (agrA, agrC, and agrD) rather than suppressing the motility- and flagella-associated genes (degU, motB, and flaA). This study revealed that sub-MICs of natural antimicrobial compounds reduced biofilm formation by suppressing the quorum sensing system rather than by inhibiting flagella formation.

Silver nanoparticles (Ag NPs) are extensively used as an antibacterial additive in commercial products and their release has caused environmental risk. However, conventional methods for the toxicity detection of Ag NPs are very time consuming and the mechanisms of action are not clear. We developed a new, in situ, rapid, and sensitive fingerprinting approach, using surface-enhanced Raman spectroscopy (SERS), to study the antibacterial activity and mechanism of Ag NPs of 80 and 18 nm (Ag80 and Ag18, respectively), by using the strong electromagnetic enhancement generated by Ag NPs. Sensitive spectra changes representing various biomolecules in bacteria were observed with increasing concentrations of Ag NPs. They not only allowed SERS to monitor the antibacterial activity of Ag NPs of different sizes in different water media but also to study the antibacterial mechanism at the molecular level. Ag18 were found to be more toxic than Ag80 in water, but their toxicity declined to a similar level in the PBS medium. The antibacterial mechanism was proposed on the basis of a careful identification of the chemical origins by comparing the SERS spectra with model compounds. The dramatic change in protein, hypoxanthine, adenosine, and guanosine bands suggested that Ag NPs have a significant impact on the protein and metabolic processes of purine. Finally, by adding nontoxic and SERS active Au NPs, SERS was successfully utilized to study the action mode of the NPs unable to produce an observable SERS signal. This work opens a window for the future extensive SERS studies of the antibacterial mechanism of a great variety of non-SERS-active NPs.

Modulating bacterial virulence: The role of food-plant essential oils in counteracting foodborne pathogen threats - A systematic review.

Methicillin-resistant Staphylococcus aureus (MRSA) infections have become arduous to treat due to their capacity to form biofilms, develop persistence, and exhibit significant antimicrobial resistance. These factors contribute to the complexity of managing MRSA infections and highlight the urgent need for innovative treatment strategies. This endeavor aims to evaluate the safety of 2,2'-Bipyridine (2,2'-Bipy) derivatives and their antimicrobial, anti-biofilm, and anti-persister activities in treating MRSA Infections. Six derivatives were screened for their ADMET properties and tested for minimum inhibitory concentrations against various bacterial strains using agar well diffusion and broth dilution. Safety studies were conducted through hemolysis tests, cell viability assays, and in vivo acute oral toxicity examinations. Bactericidal mechanisms and biofilm disruption effects were analyzed using crystal violet staining and confocal microscopy assays. The murine thigh infection model was also used to investigate the in vivo efficacy. All derivatives exhibited favorable physicochemical profiles and ADMET properties and are predicted to be safe based on their drug-like properties. in vitro studies demonstrated that derivatives are non-toxic to 3T3 L1, and in vivo studies confirmed their safety in mice at a dose of 300 mg/kg and their non-hemolytic nature against rabbit red blood cells. All compounds showed potent antibacterial activity against the tested bacteria, including the resistant MRSA strain 831. They inhibited biofilm formation and eradicated biofilms in a dose-dependent manner against MTCC 737 and MRSA 831, and they effectively eliminated MRSA persister cells, outperforming the reference antibiotic vancomycin. These derivatives were found to depolarize the mitochondrial membrane and accumulate intracellular reactive oxygen species. These derivatives significantly reduced the bacterial load in the murine thigh infection model. The study concluded that 2,2'-Bipy derivatives possess significant antimicrobial activity, are non-toxic, and are effective in inhibiting biofilm formation and killing persister cells.