Promising Antibiotic Research Articles

In Vitro Susceptibility of Clinical Isolates to Ceftriaxone Alone and Ceftriaxone in Combination With Sulbactam or Tazobactam: A Comparative Study of Broad-Spectrum β-Lactam Antibiotics in India.

Background This study was designed to evaluate the current in vitro susceptibility of clinical isolates to broad-spectrum β-lactam antibiotics. Methodology Bacterial isolates, cultured from 180 non-repetitive clinical samples between April and November 2022 at three hospitals in India, were used to evaluate the minimum inhibitory concentration (MIC) of broad-spectrum β-lactam antibiotics using the Epsilometer test (E-test) method. Test antibiotics were ceftriaxone and ceftriaxone in combination with β-lactamase inhibitors (BLIs) sulbactam and tazobactam. Comparator antibiotics included amoxicillin + BLI clavulanic acid, piperacillin + tazobactam, cefotaxime, and cefepime. The MIC values obtained were used to assess the susceptibility of the isolates and to compute the efficacy ratios (ERs) of the antibiotics. Results Among the 180 clinical isolates, ~89% were gram-negative bacteria, the most prevalent ones being Escherichia coli and Klebsiella pneumoniae. Of the gram-negative isolates, ~37% were susceptible/intermediately susceptible to ceftriaxone, and ~29% were susceptible to ceftriaxone + BLIs. The test antibiotics had ER >10 against 85%-95% E. coli isolates, whereas comparator antibiotics had ER >10 against 31%-68% isolates. The differences between the test antibiotics and piperacillin + tazobactam or cefotaxime were statistically significant. Ceftriaxone, ceftriaxone + sulbactam, and ceftriaxone + tazobactam had ER >10 against 78%, 100%, and 90% of K. pneumoniae isolates, while the corresponding percentages for cefotaxime, piperacillin + tazobactam, and cefepime were 100%, 64%, and 80%, respectively. The difference between ceftriaxone + BLIs and piperacillin + tazobactam was statistically significant. Ceftriaxone + BLIs had ER >10 against all E. coli isolates producing extended-spectrum β-lactamases (ESBLs); the percentage of isolates was significantly higher than that for piperacillin + tazobactam. Ceftriaxone + tazobactam had ER >10 against all ESBL-producing K. pneumoniae isolates; ceftriaxone and ceftriaxone + sulbactam had ER ranging 6-10. Conclusions Ceftriaxone and ceftriaxone in combination with sulbactam and tazobactam are promising antibiotics to explore against prevalent infectious microorganisms such as E. coli and K. pneumoniae. Ceftriaxone + tazobactam also holds promise against ESBL-producing variants.

Echinomycin: A Journey of Challenges

Echinomycin is a natural compound discovered and isolated from bacteria, introduced as a promising antibiotic and anticancer therapy. However, it failed clinically due to improper formulations and a short half-life. After the unsuccessful clinical trials, echinomycin was overlooked. Recently, a new mechanism of action has given some hope for reviving echinomycin as an inhibitor of hypoxia-inducible factor (HIF-1). In 2015, echinomycin received orphan drug designation for treating acute myeloid leukemia in the USA. Furthermore, advancements in drug delivery systems have provided new prospects to overcome the echinomycin formulation issues and explore further therapeutic benefits. This review details the echinomycin journey along with the main challenges of this potent drug and provides insights into possible future clinical applications.

The effect of stabilized culture of Lactobacillus rhamnosus GCC-3 on gut and liver health, and anti-viral immunity of zebrafish

Probiotics are promising antibiotics alternatives to improve growth and disease resistance of cultured fish. Our study aimed to investigate the effect of dietary stabilized culture of Lactobacillus rhamnosus GCC-3 on growth performance, gut and liver health and anti-viral ability of zebrafish (Danio rerio). Zebrafish (0.161 ± 0.001 g) were fed control and the experimental diet containing 1% GCC-3 culture (1 × 107 CFU/g diet) for four weeks. Growth performance and gut and liver health parameters were monitored after four weeks feeding. The gut microbiota was analyzed by 16S rRNA gene sequencing. In another experiment, zebrafish (0.212 ± 0.001 g) were fed with basal or GCC-3 diets and challenged by spring viremia of carp virus (SVCV) at the end of feeding. The antiviral immune response was evaluated at 2nd and 4th days post SVCV infection and survival rate was calculated 14 days after challenge. The results showed that adding 1% GCC-3 significantly improved growth performance of zebrafish (P < 0.05). The intestinal expression of hypoxia-inducible factor Hif-1α, tight junction protein ZO-1α and ZO-1β was significantly up-regulated in 1% GCC-3 group compared with control (P < 0.05). Besides, 1% GCC-3 decreased the content of MDA and increased total antioxidant capacity in the intestine, and the relative expression of SOD, GST and Gpxa was improved. The abundance of Proteobacteria was reduced while Firmicutes was enriched in the intestinal microbiota of 1% GCC-3 group compared with control (P < 0.05). Zebrafish fed 1% GCC-3 showed higher survival rate after SVCV challenge. Accordingly, the expression of antiviral genes in the spleen was increased at 2nd and 4th days post infection. In conclusion, our results indicate that dietary 1% GCC-3 supplementation can improve gut and liver health as well as antiviral immunity of zebrafish.

Streptomyces iakyrus TA 36 as First-Reported Source of Quinone Antibiotic γ-Rubromycin.

A wide range of bioactive compounds with potential medical applications are produced by members of the genus Streptomyces. A new actinomycete producer of the antibiotic γ-rubromycin, designated TA 36, was isolated from an alpine soil sample collected in Peru (Machu Picchu). Morphological, physiological and biochemical characteristics of the strain, together with data obtained via phylogenetic analysis and MALDI-TOF MS, were used for the correct identification of the isolate. The isolate TA 36 showed morphological characteristics that were consistent with its classification within the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences showed that the TA 36 strain was most similar to S. iakyrus and S. violaceochromogenes with 99% similarity. Phylogenetic analysis together with the profile of whole cell proteins indicated that the strain tested could be identified as S. iakyrus TA 36. The crude extract Ext.5333.TA 36 showed various effects against the tested organisms with strong antimicrobial activity in the growth of Staphylococcus aureus (Newman) (MIC value of 0.00195 µg/µL). HPLC fractionation and LC/MS analysis of the crude extract led to the identification of the quinone antibiotic γ-rubromycin, a promising antitumour and antibacterial antibiotic. To the best of our knowledge, there is currently no report on the production of γ-rubromycin by S. iakyrus. Therefore, this study suggests S. iakyrus TA 36 as the first-reported source of this unique bioactive secondary metabolite.

Enzymatic reconstitution of salicylate formation in promysalin biosynthesis

Promysalin is an amphipathic antibiotic isolated from Pseudomonas promysalinigenes (previously Pseudomonas putida RW10S1) which shows potent antibacterial activities against Gram-negative pathogens by inactivating succinate dehydrogenase. Based on the in-vivo studies, promysalin is hypothesized to be assembled from three building blocks: salicylic acid, proline, and myristic acid via a proposed but uncharacterized hybrid NRPS-PKS biosynthetic pathway. So far, no in-vitro biosynthetic studies have been reported for this promising antibiotic. Here, we report the first in-vitro reconstitution and biochemical characterization of two early enzymes on the pathway: PpgH, an isochorismate synthase (IS), and PpgG, an isochorismate pyruvate lyase (IPL) which are involved in the biosynthesis of salicylic acid, the polar fragment of promysalin. We also report a secondary chorismate mutase (CM) activity for PpgG. Based on our biochemical experiments, preliminary mechanistic proposals have been postulated for PpgH and PpgG. We believe this study will lay a strong foundation for elucidating the functions and mechanisms of other intriguing enzymes of the promysalin biosynthesis pathway, which may potentially unravel interesting enzyme chemistries and promote pathway engineering in the future.

Identification of promising methionine aminopeptidase enzyme inhibitors: A combine study of comprehensive virtual screening and dynamics simulation study

Methionine aminopeptidase (MetAP) enzymes play a critical role in bacterial cell survival by cleaving formyl-methionine initiators at N-terminal of nascent protein, a process which is vital in proper protein folding. This makes MetAP an attractive and novel antibacterial target to unveil promising antibiotics. In this study, the crystal structure of R. prowazekii MetAP was used in structure-based virtual screening of drug libraries such as Asinex antibacterial library and Comprehensive Marine Natural Products Database (CMNPD) to identify promising lead molecules against the enzyme. This shortlisted three drug molecules; BDE-25098678, BDE-30686468 and BDD_25351157 as most potent leads that showed strong binding to the MetAP enzyme. The static docked conformation of the compounds to the MetAP was reevaluated in molecular dynamics simulation studies. The analysis observed the docked complexes as stable structure with no major local or global deviations noticed. These findings suggest the formation of strong intermolecular docked complexes, which showed stable dynamics and atomic level interactions network. The binding free energy analysis predicted net MMGBSA energy of complexes as: BDE-25098678 (-73.41 kcal/mol), BDE-30686468 (-59.93 kcal/mol), and BDD_25351157 (-75.39 kcal/mol). In case of MMPBSA, the complexes net binding energy was as; BDE-25098678 (-77.47 kcal/mol), BDE-30686468 (-69.47 kcal/mol), and BDD_25351157 (-75.6 kcal/mol). Further, the compounds were predicted to follow the famous Lipinski rule of five and have non-toxic, non-carcinogenic and non-mutagenic profile. The screened compounds might be used in experimental test to highlight the real anti- R. prowazekii MetAP activity.

Design, synthesis, and evaluation of novel pleuromutilin aryl acrylate derivatives as promising broad-spectrum antibiotics especially for combatting multi-drug resistant gram-negative bacteria

The emergence of drug-resistant strains presents a grave challenge for traditional antibiotics, underscoring the exigency of exploring novel antibacterial drugs. To address this, the present study endeavors to design and synthesize a collection of pleuromutilin aromatic acrylate derivatives, guided by combination principles. The antibacterial activity and structure-activity relationship of these derivatives were evaluated, and most of the derivatives displayed moderate to excellent antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. Among these derivatives, 5g exhibited the strongest antibacterial activity, with MIC (minimum inhibitory concentration) values ranging from 1–32 μg/mL, and a MIC value against clinically isolated drug-resistant strains of 4–64 μg/mL. Additionally, 5g exhibited negligible cytotoxicity, superior anti-mycoplasma activity, and a greater propensity to perturb bacterial cell membranes. Notably, the administration of 5g resulted in an increased survival rate of MRSA (Methicillin-resistant Staphylococcus aureus)-infected mice, with an ED50 (median effective dose) value of 9.04 mg/kg. These results indicated the potential of 5g to be further developed as an antibacterial drug for the clinical treatment of drug-resistant bacterial infections.

Novel gonorrhea strain in the United States of America leading to increase of sexually transmitted diseases load: is it an outcome of inexorable process of developing antibiotic resistance?

Novel gonorrhea strain in the United States of America leading to increase of sexually transmitted diseases load: is it an outcome of inexorable process of developing antibiotic resistance?

Method Development and Stability Indicating Studies of Marbofloxacin a Promising Antibiotic for Veterinary Use

This comprehensive review focuses on stability-indicating studies and method development validation for the estimation of Marbofloxacin, a widely used antibiotic in veterinary medicine. The stability-indicating studies assess thebehavior of Marbofloxacin drug degradation under various conditions of stress, while method development validation ensures the reliability and accuracy of analytical methods used to quantify Marbofloxacin as tablet formulations. This review provides a detailed analysis of the key aspects involved in stability-indicating studies &amp; method development validation for its estimation

Mutation in the two-component regulator BaeSR mediates cefiderocol resistance and enhances virulence in Acinetobacter baumannii.

Acinetobacter baumannii has become one of the most challenging pathogens in many countries with limited treatment options available. Cefiderocol, a novel siderophore-conjugated cephalosporin, shows potent in vitro activity against A. baumannii, including isolates resistant to carbapenems. To date, few reports on the mechanisms of cefiderocol resistance are available. In order to investigate potential mechanisms of cefiderocol resistance in A. baumannii, we performed in vitro evolution experiments at sub-lethal concentrations of the antibiotic. All four cefiderocol-resistant strains obtained harbored mutations in two-component system BaeS-BaeR. When we engineered the mutations of BaeS (D89V) and BaeR (S104N) into the genome of ATCC 17978, these mutations increased cefiderocol minimum inhibitory concentrations (MICs) by 8-fold to 16-fold. Transcriptome analyses showed that the expression of MacAB-TolC and MFS transporters was up-regulated in BaeSR mutants. Strains over-expressing MFS transporter and MacAB-TolC displayed higher MICs and higher median inhibition concentration (IC50) values, while MICs and IC50 decreased when efflux pump genes were knocked out. In a BaeR mutant with up-regulated csu operon, we observed a higher number of pili, enhanced surface motility, and increased biofilm formation compared to wild-type ATCC 17978. Using the Galleria mellonella infection model, we found that the BaeS mutant in which paa operon was up-regulated exhibited increased virulence. In conclusion, the mutations in BaeSR decreased cefiderocol susceptibility of A. baumannii through up-regulating efflux pumps gene expression. BaeS or BaeR also controls the expression of csu and paa, influencing biofilm formation, surface motility, and virulence in A. baumannii. IMPORTANCE The widespread prevalence of multi-drug-resistant A. baumannii (MDRAB) poses a significant therapeutic challenge. Cefiderocol is considered a promising antibiotic for the treatment of MDRAB infections. Therefore, it is necessary to study the potential resistance mechanisms of cefiderocol to delay the development of bacterial resistance. Here, we demonstrated that mutations in baeS and baeR reduced the susceptibility of A. baumannii to cefiderocol by up-regulating the expression of the MFS family efflux pump and MacAB-TolC efflux pump. We propose that BaeS mutants increase bacterial virulence by up-regulating the expression of the paa operon. This also reports the regulatory effect of BaeSR on csu operon for the first time. This study provides further insights into the role of BaeSR in developing cefiderocol resistance and virulence in A. baumannii.

Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens.

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process.

#5984 IDENTIFICATION OF AN ANTIBIOTIC-TREATED MOUSE MODEL TO STUDY THE GUT-KIDNEY AXIS

Abstract Background and Aims Microbiota and its modulation could influence several physiological functions, and there is growing interest in it as a cutting-edge research topic in the field of renal diseases. According to the literature, germ-free (GF) mice are the gold-standard animal model for studying the correlation between the changing microbiota and the effects in the host. Unfortunately, their generation and maintenance are often unfeasible and costly, and the lack of microbiota could influence the circulating levels of amino acids, thus affecting kidney growth. This study aims to identify a more advantageous mouse model, specifically an antibiotic-treated one, that exhibits a strong reduction of the gut microbiota without compromising the kidney functionality. Method Five-six weeks old C57/BL6 male mice were randomly divided into 5 groups: Group 1 (Tr1) received a cocktail containing ampicillin, gentamicin, metronidazole, neomycin (1mg/mL each) and vancomycin (0.5 mg/mL) by oral gavage for 10 days; Group 2 (Tr2) received drinking water (DW) supplemented with ampicillin (1 mg/mL) neomycin (1 mg/mL), metronidazole (1mg/mL) and vancomycin (0,5 mg/mL) for 14 days; Group 3 (Comb3) was treated with amphotericin-B (0.2 mg/mL) by oral gavage for 3 days followed by an antibiotic cocktail composed by vancomycin (10 mg/mL), neomycin (20 mg/mL), metronidazole (20 mg/mL) and amphotericin-B (1 mg/mL) administrated by oral gavage and ampicillin (1 mg/mL) provided in DW for 7 days; Group 4 (Comb4) was treated with a combination of ampicillin, neomycin, metronidazole and vancomycin (40mg/mL each) both by oral gavage and DW; Control Group (Ctr) received milliQ water only. Fecal DNA was used to assess the reduction of the intestinal microbiota by the 16S gene rRNA sequencing, and intestinal permeability was determined both in vivo by FITC-dextran and by measuring the expression of Zonulin-1 (ZO-1) on intestine sections. To verify the kidney integrity after treatment, renal morphology and fibrosis were evaluated by multiphoton microscopy, while transdermal measurement of GFR occurred by using MediBeacon device. Results Apart from Tr1, with the less percentage of microbiota depletion, the rest of antibiotics cocktails exhibited a significant microbiota reduction. Data regarding intestinal permeability in vivo by FITC-dextran were consistent with hematoxylin-eosin staining and revealed a reduced expression of ZO-1 in all antibiotics-treated groups versus Ctr, confirming that microbiota has been depleted as expected. In all the experimental groups, particularly Tr2, urine/serum parameters reestablished at Ctr levels after recovery and only Comb4 showed signs of fibrosis. The low intragroup variability and the homogeneous decrease of the most abundant phyla, as well as renal physiology evaluation, point to Tr2 as the most promising antibiotics cocktail among the tested ones. Conclusion The potential of our study lies in the feasibility to have a manageable mouse model to perform studies on the gut-kidney axis. In particular, it will be specifically used for the evaluation of fecal microbiota transplant (FMT) with feces of patients affected by kidney diseases, enabling us to determine whether intestinal dysbiosis may impair the kidney functionality. However, the characterized mouse model might be employed to assess the effect of the FMT from patients with renal pathologies not only on kidneys but also at systemic level.

In Vitro Activity of Omadacycline and Comparator Antibiotics against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae Urinary Isolates.

Limited oral antibiotic options exist for urinary tract infections (UTI) caused by ESBL-producing Enterobacterales. The aim of the study was to evaluate in vitro activity of omadacycline and comparator antibiotics against clinical ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae urinary isolates. 102 isolates each of E. coli and K. pneumoniae were collected from clinical urine specimens in 2019. By design, an equal number of each species were included that tested positive and negative for ESBL production. Omadacycline MICs were determined using gradient test strips and compared to MICs of comparator antibiotics as determined by an automated broth microdilution system. Isolates were considered susceptible to omadacycline if the MIC was ≤4 µg/mL for each species. 54.9% of all ESBL-producing isolates were susceptible to omadacycline, but better susceptibility was observed for ESBL-producing E. coli (74.5%). Omadacycline MICs were 2-4 fold lower for E. coli and K. pneumoniae strains not producing ESBL. The omadacycline MIC 50 and 90 values were 4 and 16 µg/mL, respectively, for all isolates studied. 74.5% of all isolates were considered susceptible to omadacycline. MICs were generally lower for E. coli strains with MIC 50 and 90 values of 4 and 8 µg/mL, respectively (87.3% susceptible), compared with K. pneumoniae. Overall, the most active agents were omadacycline and nitrofurantoin, while other comparator antibiotics were less active. Omadacycline represents a promising oral antibiotic for treating UTI caused by ESBL-producing E. coli, particularly when resistance limits other oral options. Prospective, controlled clinical trials are needed to validate these in vitro results.

High-Throughput Screening of Natural Product and Synthetic Molecule Libraries for Antibacterial Drug Discovery.

Due to the continued emergence of resistance and a lack of new and promising antibiotics, bacterial infection has become a major public threat. High-throughput screening (HTS) allows rapid screening of a large collection of molecules for bioactivity testing and holds promise in antibacterial drug discovery. More than 50% of the antibiotics that are currently available on the market are derived from natural products. However, with the easily discoverable antibiotics being found, finding new antibiotics from natural sources has seen limited success. Finding new natural sources for antibacterial activity testing has also proven to be challenging. In addition to exploring new sources of natural products and synthetic biology, omics technology helped to study the biosynthetic machinery of existing natural sources enabling the construction of unnatural synthesizers of bioactive molecules and the identification of molecular targets of antibacterial agents. On the other hand, newer and smarter strategies have been continuously pursued to screen synthetic molecule libraries for new antibiotics and new druggable targets. Biomimetic conditions are explored to mimic the real infection model to better study the ligand-target interaction to enable the designing of more effective antibacterial drugs. This narrative review describes various traditional and contemporaneous approaches of high-throughput screening of natural products and synthetic molecule libraries for antibacterial drug discovery. It further discusses critical factors for HTS assay design, makes a general recommendation, and discusses possible alternatives to traditional HTS of natural products and synthetic molecule libraries for antibacterial drug discovery.

Optimisation and identification of anchovy antimicrobial peptides by enzymolysis and untargeted proteomic profiling

Natural antimicrobial peptides are promising antibiotics without inducing high bacteria resistance and have wide applications in the medical health and food industry. Herein, we prepared and optimised anchovy antimicrobial peptides (AAMPs) by degreasing and enzymolysis of anchovy extracts under different conditions. The enzymolysis mixtures at optimised preparation conditions exhibited concentration-dependent inhibitory activity against Staphylococcus aureus. Then, we applied the mass spectrometry-based proteomics analysis to globally profile the peptide constitutes within the active peptide mixture and finally, 4 unique peptides coming from 68 proteins were confidently identified. We compared the peptide sequences with the antimicrobial peptides (AMPs) database and synthesised 4 potential AAMPs. As a result, peptide GTEDELDKY exhibited inhibitory activity against Escherichia coli, and peptides DREGESGPS, YIGRPIPQ and YEDEINKR exhibited inhibitory activity against SA. Our work established a useful workflow for discovering novel AMPs from fish proteins, which may play important role in the development of effective antibiotics.

Evaluation of Antibacterial activity of aqueous extract of Cucumis melo

Plant-based phytochemicals are promising antibiotics for treating microbial illnesses in humans. The purpose of the current study is to assess the antibacterial properties of an aqueous Cucumis melo extract against Bacillus subtilis and Escherichia coli. The Agar well diffusion method is initially used to assess the antibacterial activity of the fruit's aqueous extract against the gram’s positive B. subtilis and the gram’s negative organism E. coli. Results reveal that, in comparison to the control, the Cucumis melo aqueous fruit extract at two dose levels of 200 µg/ml and 400µg/ml significantly increases the zone of inhibition of microorganisms. Additionally, a very large zone of inhibition was seen at 400µg/ml dosage. The difference between the mean values of 200 and 400µg/ml was also encouraging. The aqueous extract exhibits a considerable dose, in conclusion.

Efficient in planta production of amidated antimicrobial peptides that are active against drug-resistant ESKAPE pathogens

Antimicrobial peptides (AMPs) are promising next-generation antibiotics that can be used to combat drug-resistant pathogens. However, the high cost involved in AMP synthesis and their short plasma half-life render their clinical translation a challenge. To address these shortcomings, we report efficient production of bioactive amidated AMPs by transient expression of glycine-extended AMPs in Nicotiana benthamiana line expressing the mammalian enzyme peptidylglycine α-amidating mono-oxygenase (PAM). Cationic AMPs accumulate to substantial levels in PAM transgenic plants compare to nontransgenic N. benthamiana. Moreover, AMPs purified from plants exhibit robust killing activity against six highly virulent and antibiotic resistant ESKAPE pathogens, prevent their biofilm formation, analogous to their synthetic counterparts and synergize with antibiotics. We also perform a base case techno-economic analysis of our platform, demonstrating the potential economic advantages and scalability for industrial use. Taken together, our experimental data and techno-economic analysis demonstrate the potential use of plant chassis for large-scale production of clinical-grade AMPs.

Antibacterial effect of Cannabidiol oil against Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis and level of toxicity against Artemia salina

Acne is one of the most common skin pathologies; one of the causes is Propionibacterium acnes, an anaerobic and gram-positive microorganism that lives in the hair follicles of the skin and currently presents resistance to antibiotic-based treatments; this research topic has the purpose of evaluating the antibiotic activity of Cannabidiol oil against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis and the level of toxicity against Artemia salina. For the methodology, antibiograms were used by the Kirby-Bauer method, where the concentrations were evaluated: 0,8 %; 0,6 %; 0,4 %; 0,3 % and 0,1 %; Amoxicillin for positive control and Dimethyl sulfoxide (DMSO) for negative control; the percentage of inhibition against Propionibacterium acnes and two control bacteria were calculated: Staphylococcus aureus and Staphylococcus epidermidis. Once the percentage of inhibition was tested, a toxicity study was carried out against Artemia salina to determine its LD50. The Cannabidiol oil obtained from the Ecuadorian company was used as the antibiotic agent to be evaluated, and it was found that at a concentration of 0,8%, it presented a percentage of inhibition of 91,2 %; 98,7 % and 93,6 % against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis, respectively, data that do not present a significant difference against Amoxicillin; for the Artemia salina test, an LD50 of 4,8 % was obtained; taking into account that the commercial oil has a presentation of 1,6 % (500 mg/30 mL), it results in a relatively innocuous product. Thus concluding that Cannabidiol oil is a very promising antibiotic due to the inhibition percentages presented and low toxicity. Keywords: CBD, antibiograms, bioassay, LD50.

Cinacalcet exhibits rapid bactericidal and efficient anti-biofilm activities against multidrug-resistant Gram-positive pathogens

Infections caused by Gram-positive bacteria pose a serious threat to global public health. Drug resistance, dormant persister cells, and biofilm formation are the key challenges affecting the efficacy of antibiotics against Gram-positive bacterial infections. In this study, cinacalcet exhibited good inhibitory activity against multidrug-resistant Gram-positive bacteria, with minimum inhibitory concentrations (MICs) ranging from 3.13μg/mL to 25μg/mL. Cinacalcet displayed more rapid and stronger bactericidal activity against planktonic and persister cells of Staphylococcus aureus and Enterococcus faecalis compared with the antibiotics vancomycin or ampicillin, as well as potent inhibition and eradication of mature biofilms of methicillin-resistant S.aureus (MRSA) and linezolid-resistant E.faecalis (LRE). In addition, the robust antibacterial activity was demonstrated invivo by a pneumonia infection model and a biofilm formation and deep-seated infection model. Collectively, these findings indicate that cinacalcet may be a promising new candidate antibiotic to combat infections caused by multidrug-resistant Gram-positive pathogens.

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus.

LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98. The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values. LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2-4 µg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED50 value of 0.41-1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (Cmax) 11,466.67-48,866.67 ng/mL, area under the concentration-time curve from 0 to 24 h (AUC0-24) 14,788.42-91,885.93 ng/mL·h, and elimination half-life (T1/2) 1.70-2.64 h, respectively. Cmax/MIC (R 2 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log 10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.