Broad-spectrum Activity Research Articles

Biocontrol potential of natamycin-producing Streptomyces lydicus JCK-6019 against soil-borne fungal diseases of cucumber and characterization of its biocontrol mechanism.

Fusarium oxysporum f. sp. cucumerinum and Rhizoctonia solani AG-4 are the two most important fungal pathogens causing soil-borne fungal diseases of cucumber; they are difficult to control and cause serious economic losses. Given the detrimental effects of the indiscriminate use of chemical fungicides, biocontrol emerges as an efficient and ecofriendly alternative for managing soil-borne fungal diseases. Streptomyces lydicus JCK-6019 (hereafter, JCK-6019) was isolated from rhizosphere soil. Its fermentation filtrate and volatile organic compounds exhibited broad-spectrum antifungal activity against various phytopathogenic fungi and oomycetes. JCK-6019 produced natamycin as an agar-diffusible antifungal metabolite. It also produced indole-3-acetic acid and various hydrolytic enzymes. In vivo experiments revealed that a ten-fold-diluted optimized JCK-6019 fermentation broth exhibited 100% control efficiency against cucumber damping-off disease and 62.5% control efficiency against cucumber Fusarium wilt disease. Pretreatment of cucumber seedlings with 1000-fold-diluted optimized JCK-6019 fermentation broth resulted in 68.18% and 23.91% disease control values against cucumber damping-off and Fusarium wilt disease, respectively. Moreover, peroxidase activity in cucumbers after 1 day of treatment was 1.5-fold higher than that in the control. Similarly, polyphenol oxidase activity in cucumbers after 3 days of treatment was 2.34-fold higher than that in the control, indicating that JCK-6019 can induce plant resistance. The natamycin-producing strain JCK-6019 could effectively suppress the development of cucumber Fusarium wilt and damping-off disease by inducing plant resistance and producing antifungal metabolites, including natamycin and volatile organic compounds. Thus, JCK-6019 possesses high potential for application in the development of biocontrol agents against soil-borne fungal diseases of cucumber. © 2024 Society of Chemical Industry.

High-Efficiency Broad-Spectrum Antibacterial Activity of Chitosan/Zinc Ion/Polyoxometalate Composite Films for Water Treatment.

The development of multifunctional films with rapidly killing microorganisms and adsorbing residual antibiotics in wastewater remains a challenging endeavor. In this work, the chitosan/zinc ion/polyoxometalate (CS/Zn2+/POM) multifunctional films were prepared by the freeze-drying method using chitosan, ZnO, and POM. Notably, the CS/Zn2+/POM films exhibited excellent bactericidal properties against Gram-positive/negative bacterial strains including Staphylococcus aureus (S. aureus, 99.80%), Escherichia coli (E. coli, 99.82%), and drug-resistant E. coli bacterial strains (kanamycin-resistant E. coli, 87.76% and ampicillin-resistant E. coli, 99.71%). This may be due to the chelation of Zn2+ with CS disrupting the cell membrane and bringing POM into direct contact with bacteria, leading to bacterial death. In addition, the CS/Zn2+/POM films showed good adsorption performance to a tetracycline (TC) solution (adsorption rate 75.2%). Further studies showed that the main process of tetracycline removal by CS/Zn2+/POM films was controlled by a physical adsorption. This POM-based film material has an important potential for the synthesis of broad-spectrum antimicrobial materials for the removal of residual antibiotics from water pollutants such as tetracycline.

High-Throughput Screening of More Than 30,000 Compounds for Anthelmintics against Gastrointestinal Nematode Parasites.

Gastrointestinal nematodes (GINs) are among the most common parasites of humans, livestock, and companion animals. GIN parasites infect 1-2 billion people worldwide, significantly impacting hundreds of millions of children, pregnant women, and adult workers, thereby perpetuating poverty. Two benzimidazoles with suboptimal efficacy are currently used to treat GINs in humans as part of mass drug administrations, with many instances of lower-than-expected or poor efficacy and possible resistance. Thus, new anthelmintics are urgently needed. However, screening methods for new anthelmintics using human GINs typically have low throughput. Here, using our novel screening pipeline that starts with human hookworms, we screened 30,238 unique small molecules from a wide range of compound libraries, including ones with generic diversity, repurposed drugs, natural derivatives, known mechanisms of action, as well as multiple target-focused libraries (e.g., targeting kinases, GPCRs, and neuronal proteins). We identified 55 compounds with broad-spectrum activity against adult stages of two evolutionary divergent GINs, hookworms (Ancylostoma ceylanicum) and whipworms (Trichuris muris). Based on known databases, the targets of these 55 compounds were predicted in nematode parasites. One novel scaffold from the diversity set library, F0317-0202, showed good activity (high motility inhibition) against both GINs. To better understand this novel scaffold's structure-activity relationships (SAR), we screened 28 analogs and created SAR models highlighting chemical and functional groups required for broad-spectrum activity. These studies validate our new and efficient screening pipeline at the level of tens of thousands of compounds and provide an important set of new GIN-active compounds for developing novel and broadly active anthelmintics.

Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile.

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H3 and H4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M1, M2, and M4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.

Ceftobiprole Medocaril: A New Fifth-Generation Cephalosporin.

The objective was to review the pharmacology, efficacy, and safety of intravenous ceftobiprole in the treatment of bloodstream infections, acute bacterial skin and skin structure infections (ABSSSIs), community-acquired pneumonia (CAP), and hospital-acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP). PubMed and ClinicalTrials.gov were searched using the following terms: ceftobiprole, ceftobiprole medocaril, ceftobiprole medocaril sodium, Zevtera, and BAL5788. Articles published in English between January 1985 and August 15, 2024, related to pharmacology, safety, efficacy, and clinical trials were reviewed. Ceftobiprole has shown similar efficacy to comparator antibiotics in CAP, ABSSSIs, and bloodstream infections. Overall treatment success in patients with bacteremia was 69.8% and 68.7%; 91.3% and 88.1% with ABSSSIs and 86.6% and 87.4% with CAP in ceftobiprole and comparator groups, respectively. Finally, in the management of HAP and VAP, ceftobiprole was inferior in the VAP population. Ceftobiprole had a favorable safety profile with gastrointestinal adverse effects occurring more frequently than comparators. Clinicians have limited options to treat multidrug-resistant infections. Ceftobiprole has demonstrated efficacy against causative pathogens in specific infections including methicillin-resistant Staphylococcus aureus bacteremia (SAB), ABSSSI, and CAP and may be considered a viable alternative. However, ceftobiprole's impact on HAP, VAP, and febrile neutropenia needs to be further delineated. Ceftobiprole's broad-spectrum activity makes it a viable option for treating patients hospitalized with CAP, ABSSSI, and SAB. Further studies are needed in severely ill HAP or VAP, febrile neutropenia, and pediatric patients.

Synthesis and Antibacterial Activity of New 6″-Modified Tobramycin Derivatives

Objectives: Aminoglycosides are one of the first classes of natural antibiotics which have not lost relevance due to their broad spectrum of action against Gram-positive, Gram-negative bacteria and mycobacteria. The high growth rate of antimicrobial resistance (AMR) together with the severe side effects of aminoglycosides increase the importance of developing improved semisynthetic derivatives. Methods: In this work, we proposed a synthetic route to new tobramycin derivatives modified at the 6″-position with aminoalkylamine or guanidinoalkylamine residues. Results: The antibacterial activity of the new compounds against reference strains of microorganisms was comparable to the parental tobramycin. In striking contrast to tobramycin (resistance index, >256), its 6″-modified derivatives were significantly more potent against resistant clinical isolates of P. aeruginosa strains (resistance index = 4–16) and they demonstrated a promising AMR circumvention in E. coli strains associated with mutations in the fusA gene encoding elongation factor G. All the obtained tobramycin derivatives exhibited reduced cytotoxicity for the eukaryotic HEK293T cells compared to the tobramycin and thereby they potentially may have improved therapeutic index. The proposed modification of the 6″-position of tobramycin does not change the mechanism of aminoglycoside’s antibacterial activity: new compounds induced translation errors which resulted in the inhibition of protein synthesis in bacterial cells. Conclusions: Taken together, we can suggest that further modifications of the 6″-position of tobramycin may be beneficial for circumvention of AMR to aminoglycosides or used for conjugation with other molecules of interest.

Antimicrobial Potential of Tinospora Cordfolia (Willd.) Miers (Menispermaceae) Against Disease-Causing Clinical Bacterial Pathogens

Tinospora cordifolia is an important plant growth herb belonging to the family Menispermaceae. It is a climbing deciduous and succulent shrub considered traditional medicine in Ayurveda. It has various sources of bioactive compounds and medicinal properties that produce great varieties of secondary metabolites with a broad spectrum of biological activities. It is well known for its nutraceutical food that provides health benefits mainly due to the phytochemicals present in the plant such as alkaloids, flavonoids, proteins, and carbohydrates. It has a wide application in pharmacological research such as antitumor, antiinflammatory, Cerebro-protective, cardio-protective, immunoregulatory, Vasorelaxation, and anxiolytic. Tinospora cordifolia showed antimicrobial activity against a few pathogenic bacteria and pathogenic fungi but not many clinical bacterial pathogens and hospital-acquired infections. In this study, the author focused on the antimicrobial activity of Tinospora cordifolia against eight clinical pathogenic bacteria (Escherichia coli, Klebsiella pneumoniae, MRSA, Proteus mirabilis, Salmonella typhi, Shigella sonnei, Pseudomonas aeruginosa, Acinetobacter baumanii) isolated mainly from patient’s sample. T. cordifolia was extracted from two different solvents, methanol and water. The antimicrobial activity was determined using an agar well diffusion assay. T. cordifolia extract has antibacterial activity against all tested clinical bacterial pathogens and has the highest antibacterial activity against Salmonella typhi in all ratios of methanol concentrations (47.5μg/ml). The Minimum Inhibitory Concentration (MIC) of Tinospora cordifolia methanol extract was found at 100μg/ml. Methanol solvent concentration with the most active antibacterial activity of the extract was of different concentrations as 300μg/ml followed by 450μg/ml and 500μg/ml.

Development of an HPLC–UV method for quantification of posaconazole in low-volume plasma samples: design of experiments and machine learning models

Posaconazole (PCZ) is a triazole antifungal agent with a broad-spectrum activity. Our research aims to present a novel approach by combining a 2-level fractional factorial design and machine learning to optimize both chromatography and extraction experiments, allowing for the development of a rapid method with a low limit of quantification (LOQ) in low-volume plasma samples. The PCZ retention time at the optimized condition (organic phase 58%, methanol 6%, mobile pH = 7, column temperature: 39 °C, and flow rate of 1.2 mL/min) was found to be 8.2 ± 0.2 min, and the recovery of the PCZ at the optimized extraction condition (500 µL extraction solvent, NaCl 10% w/v, plasma pH = 11, extraction time = 10 min, and centrifuge time = 1 min) was calculated above 98%. The results of machine learning models were in line with the results of experimental design. Method validation was performed according to ICH guideline. The method was linear in the range of 50–2000 ng/mL and LOQ was found to be 50 ng/mL. Additionally, the validated method was applied to analyze PCZ nanomicelles and conduct pharmacokinetic studies on rats. Half-life (t1/2), mean residence time (MRT), and the area under the drug concentration–time curve (AUC) were found to be 7.1 ± 0.6 h, 10.5 ± 0.9 h, and 1725.7 ± 44.1 ng × h/mL, respectively.Graphical

Enhancing cancer therapy: advanced nanovehicle delivery systems for oridonin

Oridonin (ORI), an ent-kaurane diterpenoid derived from Rabdosia rubescens (Hemsl.) H.Hara, serves as the primary bioactive component of this plant. It demonstrates a broad spectrum of therapeutic activities, including moderate to potent anticancer properties, alongside anti-inflammatory, antibacterial, antifibrotic, immunomodulatory, and neuromodulatory effects, thus influencing diverse biological processes. However, its clinical potential is significantly constrained by poor aqueous solubility and limited bioavailability. In alignment with the approach of developing drug candidates from natural compounds, various strategies, such as structural modification and nanocarrier systems, have been employed to address these challenges. This review provides an overview of ORI-based nano-delivery systems, emphasizing their potential to improve the clinical applicability of oridonin in oncology. Although some progress has been made in advancing ORI nano-delivery research, it remains insufficient for clinical implementation, necessitating further investigation.

Novel Medical Countermeasures for Nerve Agent and Pharmaceutical Based Agent Poisoning

Nerve agents are organophosphorus compounds which inhibit acetylcholinesterase (AChE) enzyme. Existing AChE reactivators (Oximes) have several limitations in mean of reactivation potential, broad action spectrum, and penetration rate through blood-brain barrier. Ongoing studies focus on design and synthesis of novel oximes. Pharmaceutical based agents like fentanyl abuse becomes an important public health threat. Naloxone and naltrexone that are centrally acting opioid receptor antagonists, are used for reversing the effects of the opioid overdose.

Gatifloxacin hydrochloride confers broad-spectrum antibacterial activity against phytopathogenic bacteria

Bacterial diseases pose significant threats to agriculture and natural ecosystems, causing substantial crop losses and impacting food security. Until now, there has been a less efficient control strategy against some bacterial diseases such as bacterial wilt, caused by Ralstonia solanacearum. In this study, we screened a library of 58 microorganism-derived natural products for their antibacterial activity against R. solanacearum. Gatifloxacin hydrochloride exhibited the best inhibitory effect with an inhibition rate of 95% at 0.0625 mg/L. Further experiments demonstrate that gatifloxacin hydrochloride inhibits R. solanacearum growth in a concentration-dependent manner, with the minimum inhibitory concentration of 0.125 mg/L. Treatment with 0.5 mg/L of gatifloxacin hydrochloride killed more than 95% of bacteria. Gatifloxacin hydrochloride significantly inhibited biofilm formation by R. solanacearum. Gatifloxacin hydrochloride also shows good antibacterial activity against Pseudomonas syringae pv. tomato DC3000 and Xanthomonas campestris pv. vesicatoria. Exogenous application of gatifloxacin hydrochloride suppressed disease development caused by R. solanacearum and P. syringae. In summary, our results demonstrate the great potential of microorganism-derived compounds as broad-spectrum antibacterial compounds, providing alternative ways for the efficient control of bacterial plant diseases.

Potential applications of Bacillus thuringiensis Berliner in agriculture, medicine and environment

Bacillus thuringiensis (Bt) is renowned for its insecticidal activity against a wide range of target pests. Bt formulations offer safe alternatives to chemical insecticides, effectively eliminating insects using toxins and enzymes such as chitinases and metalloproteases. This bacterium has transformed pest management through the development of genetically modified insect-resistant crops, providing targeted protection. Beyond pest control, Bt serves as an alternative to antibiotics, fertilizers, bioremediation agents and for nanomaterial synthesis. While its effectiveness in insect control contributes to sustainable farming practices, Bt further promotes plant growth as a biofertilizer and growth enhancer. Additionally, it plays various roles in medicine and environmental applications. Bacteriocins, proteins produced by Bt, exhibit high efficacy against pathogenic bacteria and demonstrate some fungicidal activity, offering potential applications in medicine and food preservation. Bt’s influence extends to environmental bioremediation, where it targets heavy metals and dyes. It is also involved in the synthesis of metal nanoparticles and exhibits anti-cancer activity by targeting various cancerous cells. Overall, Bt showcases a broad spectrum of activity across agriculture, medicine and environmental sectors, highlighting its potential to enhance crop productivity, improve human health and reduce environmental pollution.

Bacillus methylotrophicus influences on the virulence of Aeromonas hydrophila and probiotic applications in Ctenopharyngodon idella

Probiotics are alternatives to antibiotics that resist infection and benefit the host in several aspects. Here, we isolated and identified a novel strain of Bacillus methylotrophicus (XA-8) with a broad spectrum of activity against Aeromonas hydrophila AhX040 and other aquatic bacterial pathogens. The strain was non-pathogenic as it revealed no cytotoxic effects in hepatic L8824 cells or pathophysiological signs in the tissue of Ctenopharyngodon idella (grass carp). Using a co-culture approach, XA-8 (1×109 CFU mL−1) when co-cultivated with AhX040 (1×108 CFU mL−1) revealed a reduction in the cell density, cytotoxicity, and infection rate of AhX040. More interestingly, genes such as aer, act, hylA, lafA, hcp, and luxS, associated with the virulence of AhX040, were significantly down-regulated during co-cultivation (P<0.05). Furthermore, XA-8 as a feed supplement to grass carp up-regulated the immune-related genes in the liver, spleen, kidney, and intestine. The villi length and expression level of growth-related genes in the intestine were significantly higher (P<0.05) in the XA-8 supplemented grass carp. In addition to resisting infection (52.63 %), probiotic XA-8 modulated the gut microbiota of grass carp by increasing Fusobacteriota and Bacteroidota at the phylum level, while decreasing Aeromonas at the genus level. The whole genome sequence analysis showed the strain possesses multiple gene clusters for antimicrobial substances and metabolism. Our results demonstrate that B.methylotrophicus XA-8 is a novel probiotic with potential applications for aquaculture.

Green-Synthesis of CuO and Ce-Doped CuO Nanoparticles Using Aqueous Extract of Yam Peel and their Antimicrobial Properties

The rise of drug-resistant microbes presents a critical global health challenge in the 21st century, necessitating the development of potent antimicrobial agents with broad-spectrum activity. Therefore, in this study, we explored the antimicrobial activity of copper oxide (CuO) and cerium-doped CuO (Ce-doped CuO) obtained through a facile green synthesis approach. The nanoparticles were synthesized using aqueous extract of Dioscorea spp (yam peel) and characterized for their physicochemical properties using X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), electron microscopy, and UV-Vis spectroscopy. Their antimicrobial efficacy was tested against three bacterial strains—Enterococcus faecalis, Escherichia coli, and Listeria monocytogenes—and three fungal strains—Aspergillus niger, Mucor mucedo, and Penicillium chrysogenum. The results demonstrated that cerium doping significantly altered the physicochemical properties of CuO, leading to enhanced antimicrobial activity. The antibacterial zone of inhibition ranged from 7.50 to 16.55 mm for CuO and 11.80 to 19.50 mm for Ce-doped CuO. For antifungal activity, the minimum inhibitory concentration (MIC) ranged from 0.25 to 0.30 mg/mL for CuO and 0.025 to 0.03 mg/mL for Ce-doped CuO. Notably, the Ce-doped CuO nanoparticles exhibited antimicrobial effects comparable to standard antibiotics. These findings highlight the potential of green-synthesized Ce-doped CuO nanoparticles as effective antimicrobial agents. By leveraging green synthesis and elemental doping, this study offers a promising solution to combat a wide spectrum of infectious pathogens.

Synthesis and Biological Evaluation of Amino Acid and Peptide Conjugates of 5-Bromovaleric Acid.

Among various carboxylic acid derivatives, valeric acid or pentanoic acid is found to be widely distributed in nature. It is a straight-chain alkyl carboxylic acid containing five carbon atoms. Due to the therapeutic value of valeric acid, it is used as a versatile nucleus in the pharmaceutical field. Valeric acid derivatives are associated with a broad spectrum of biological activities, like anticonvulsant, antiplatelet, antidiabetic, and plant growth activities. It has previously been revealed that peptide derivatives of carboxylic acids are accountable for enhanced antimicrobial activity. Therefore, it was hypothesized that coupling peptides with valeric acid would increase the antimicrobial properties of the target compounds. So, the objective of the present study was to synthesize peptide derivatives of 5-bromovaleric acid and evaluate their antibacterial and antifungal activities. 5-bromovaleric acid was synthesized by the reaction of cyclopentanone and hydrogen peroxide in the presence of copper bromide and sodium bromide. Additionally, 5-bromovaleric acid was coupled with amino acid methyl esters, dipeptides, tripeptides, and tetrapeptides in the presence of dicyclohexylcarbodimide (DCC) and N-methylmorpholine (NMM) as a base under continuous stirring for 36 hours to produce its peptide derivatives. The results obtained showed that 5-bromovaleric acid possesses more potent antibacterial activity than N-terminal 5-bromovaleric acid conjugates of selected di-, tri, and tetra peptide Cterminal methyl esters against ciprofloxacin as a standard. The selected dipeptide and tripeptide Nterminal 5-bromovaleric acid-conjugated C-terminal methyl ester derivatives were more active than the selected tetrapeptide methyl ester analogue. Using fluconazole as a reference, the antifungal efficacy of 5-bromovaleric acid against C. albicans and A. niger declined as it was combined with C-terminal methyl esters of selected dipeptides, tripeptides, and tetrapeptides. The novel selected peptide derivatives had less antibacterial and antifungal action than the parent 5-bromovaleric acid. Antibacterial and antifungal investigations showed that 5- bromopentanoic acid peptide derivatives might impair antimicrobial efficacy. Further, attaching 5- bromopentanoic acid to di, tri, and tetra peptides did not boost their antibacterial potential.

Fish-derived cationic antimicrobial peptide piscidin 1 exerts broad-spectrum bactericidal activities against multidrug-resistant Gram-negative pathogens

Fish-derived cationic antimicrobial peptide piscidin 1 exerts broad-spectrum bactericidal activities against multidrug-resistant Gram-negative pathogens

Extracellular vesicles of Janthinobacterium lividum as violacein carriers in melanoma cell treatment

Violacein is a natural indole-derived purple pigment of microbial origin that has attracted attention for its remarkable biological properties. Due to its poor solubility in aqueous media, most studies of this pigment use extracts of the compound obtained with common solvents. Violacein is also transported in bacterial extracellular vesicles (EVs) and transferred via this type of carrier remains stable in an aqueous environment. This paper is the first to present an in-depth study of Janthinobacterium lividum EVs as violacein carriers. J. lividum EVs were studied for their contribution to violacein translocation, size, morphology and protein composition. The production of violacein encapsulated in EVs was more efficient than the intracellular production of this compound. The average size of the violacein-containing EVs was 124.07 ± 3.74 nm. Liquid chromatography-tandem mass spectrometry analysis (LC–MS/MS) revealed 932 proteins common to three independent EVs isolations. The high proportion of proteins with intracellular localisation, which are involved in many fundamental cellular processes, suggests that J. lividum EVs could be generated in a cell lysis model, additionally stimulated by violacein production. Using human keratinocytes and melanoma cell lines, it was confirmed that J. lividum EVs are able to react with and deliver their cargo to mammalian cells. The EVs-delivered violacein was shown to retain its activity against melanoma cells, and the dose and timing of treatment can be selected to target only cancer cells. The characterisation of J. lividum EVs, described in the following paper, represents a milestone for their future potential anticancer application.Key points• This report focuses on the investigation of Janthinobacterium lividum EVs as a new delivery vehicle for violacein, a compound with a previously demonstrated broad spectrum of activity.• EVs were characterised for size, morphology and protein composition.• Studies on human keratinocytes and a melanoma cell model confirmed that the activity of violacein applied in the encapsulated form of EVs is similar to that of its organic solvent extract, but their production is much more environmentally friendly.

Evaluation of Novel HLM Peptide Activity and Toxicity against Planktonic and Biofilm Bacteria: Comparison to Standard Antibiotics.

Antibiotic resistance is one of the main concerns of public health, and the whole world is trying to overcome such a challenge by finding novel therapeutic modalities and approaches. This study has applied the sequence hybridization approach to the original sequence of two cathelicidin natural parent peptides (BMAP-28 and LL-37) to design a novel HLM peptide with broad antimicrobial activity. The physicochemical characteristics of the newly designed peptide were determined. As well, the new peptide's antimicrobial activity (Minimum Inhibitory Concentration (MIC), Minimum Bacterial Eradication Concentration (MBEC), and antibiofilm activity) was tested on two control (Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922) and two resistant (Methicillin-resistant Staphylococcus aureus (MRSA) ATCC BAA41, New Delhi metallo-beta- lactamase-1 Escherichia coli ATCC BAA-2452) bacterial strains. Furthermore, synergistic studies have been applied to HLM-hybridized peptides with five conventional antibiotics by checkerboard assays. Also, the toxicity of HLM-hybridized peptide was studied on Vero cell lines to obtain the IC50 value. Besides the percentage of hemolysis action, the peptide was tested in freshly heparinized blood. The MIC values for the HLM peptide were obtained as 20, 10, 20, and 20 μM, respectively. Also, the results showed no hemolysis action, with low to slightly moderate toxicity action against mammalian cells, with an IC50 value of 10.06. The Biomatik corporate labs, where HLM was manufactured, determined the stability results of the product by Mass Spectrophotometry (MS) and High-performance Liquid Chromatography (HPLC) methods. The HLM-hybridized peptide exhibited a range of synergistic to additive antimicrobial activities upon combination with five commercially available different antibiotics. It has demonstrated the biofilm-killing effects in the same concentration required to eradicate the control strains. The results indicated that HLM-hybridized peptide displayed a broad-spectrum activity toward different bacterial strains in planktonic and biofilm forms. It showed synergistic or additive antimicrobial activity upon combining with commercially available different antibiotics.

Unveiling the resistance risk and resistance mechanism of florylpicoxamid in Corynespora cassiicola from cucumber

Florylpicoxamid, a QiI fungicide, demonstrates broad-spectrum activity against a wide range of phytopathogenic organisms belonging to the phyla Basidiomycota and Ascomycota. Nevertheless, the potential for resistance and the underlying resistance mechanisms of Corynespora cassiicola against florylpicoxamid are still not fully understood. We determined the baseline sensitivity levels of 101C. cassiicola isolates to florylpicoxamid. The EC50 values varied from 0.01 to 1.18 μg/mL with an average of 0.50 μg/mL. Laboratory-induced fungicide adaptation of nine wild-type isolates generated seven C. cassiicola mutants exhibiting high level of resistance to florylpicoxamid, all originating from a single parental isolate. The mutants maintained their resistance even after undergoing ten successive cultivations on a medium devoid of fungicides. No cross-resistance was detected between florylpicoxamid and pyraclostrobin, fluopyram, prochloraz, or propineb. Five of the resistant mutants showed an improved compound fitness index (CFI) relative to their parental isolate, whereas the remainder displayed either a reduced or comparable CFI. All seven of the resistant mutants displayed an A37V substitution within the CcCytb protein, which was responsible for the resistance to florylpicoxamid, as validated through molecular docking analysis. Furthermore, an allele-specific PCR (AS-PCR) method for detecting the CcCytbA37V mutation was successfully established. In summarize, the findings of this study indicate a moderate risk of C. cassiicola developing resistance to florylpicoxamid, with the A37V substitution in CcCytb playing a key role in this resistance, detectable through the use of specific AS-PCR primers.

Synthesis, Biological Evaluation, and Mechanistic Insights of Rubrolide Analogues as Antitumor Agents.

Marine natural products and their analogues have as of now been acknowledged as an important source of bioactive molecules for the treatment of cancer. Rubrolides, a unique group of γ-butenolides derived from marine microorganisms, have shown strong cytotoxic activity against various tumor cells. In this study, we synthesized and characterized 21 rubrolide analogues (including 16 new compounds) and investigated their antitumor activities in order to screen more active molecules and elucidate their mechanism of action. Primary MTT assay showed that compounds 1 and 4-9 all exhibited excellent antiproliferative activities. In particular, compound 7 showed broad-spectrum cytotoxic activity against six tumor cell lines, with IC50 values mostly ranging from 2.5 to 0.2 μM. Further mechanistic studies revealed that compound 7 could penetrate HCT116 and Hela cells, localize in the endoplasmic reticulum, and upregulate the PERK-eIF2α-CHOP pathway, inducing ER stress and increasing intracellular reactive oxygen species (ROS) levels to ultimately trigger apoptosis in tumor cells. Additionally, compound 7 was found to upregulate Cyclin B1 protein expression, causing cell cycle reticulum at the G2/M phase. In vivo studies further demonstrated that liposomal delivery of compound 7 exhibited a potent antitumor efficacy against Hela xenograft tumors. Based on these results, marine-derived rubrolide analogues show significant potential as novel lead compounds for antitumor drug development.