Antibacterial Activity and Pharmacokinetic Profile of a Promising Antibacterial Agent: 22-(2-Amino-phenylsulfanyl)-22-Deoxypleuromutilin

A new pleuromutilin derivative, 22-(2-amino-phenylsulfanyl)-22-deoxypleuromutilin (amphenmulin), has been synthesized and proved excellent in vitro and in vivo efficacy than that of tiamulin against methicillin-resistant Staphylococcus aureus (MRSA), suggesting this compound may lead to a promising antibacterial agent to treat MRSA infections. In this study, the effectiveness and safety of amphenmulin were further investigated. Amphenmulin showed excellent antibacterial activity against MRSA (minimal inhibitory concentration = 0.0156~8 µg/mL) and performed time-dependent growth inhibition and a concentration-dependent postantibiotic effect (PAE). Acute oral toxicity test in mice showed that amphenmulin was a practical non-toxic drug and possessed high security as a new drug with the 50% lethal dose (LD50) above 5000 mg/kg. The pharmacokinetic properties of amphenmulin were then measured. After intravenous administration, the elimination half-life (T1/2), total body clearance (Clβ), and area under curve to infinite time (AUC0→∞) were 1.92 ± 0.28 h, 0.82 ± 0.09 L/h/kg, and 12.23 ± 1.35 μg·h/mL, respectively. After intraperitoneal administration, the T1/2, Clβ/F and AUC0→∞ were 2.64 ± 0.72 h, 4.08 ± 1.14 L/h/kg, and 2.52 ± 0.81 μg·h/mL, respectively, while for the oral route were 2.91 ± 0.81 h, 6.31 ± 2.26 L/h/kg, 1.67 ± 0.66 μg·h/mL, respectively. Furthermore, we evaluated the antimicrobial activity of amphenmulin in an experimental model of MRSA wound infection. Amphenmulin enhanced wound closure and promoted the healing of wound, which inhibited MRSA bacterial counts in the wound and decreased serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1.

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Shiga Toxin Type 1a (Stx1a) Reduces the Toxicity of the More Potent Stx2aIn VivoandIn Vitro

Infection and Immunity ◽

10.1128/iai.00787-18 ◽

2019 ◽

Vol 87 (4) ◽

Cited By ~ 7

Author(s):

Courtney D. Petro ◽

Eszter Trojnar ◽

James Sinclair ◽

Zhi-Mei Liu ◽

Mark Smith ◽

...

Keyword(s):

Shiga Toxin ◽

Lethal Dose ◽

Intraperitoneal Administration ◽

Epidemiological Data ◽

Vero Cells ◽

Oral Route ◽

Content Type ◽

Time To Death

ABSTRACTShiga toxin (Stx)-producingEscherichia coli(STEC) causes foodborne outbreaks of bloody diarrhea. There are two major types of immunologically distinct Stxs: Stx1a and Stx2a. Stx1a is more cytotoxic to Vero cells than Stx2a, but Stx2a has a lower 50% lethal dose (LD50) in mice. Epidemiological data suggest that infections by STEC strains that produce only Stx2a progress more often to a life-threatening sequela of infection called hemolytic-uremic syndrome (HUS) than isolates that make Stx1a only or produce both Stx1a and Stx2a. In this study, we found that anE. coliO26:H11 strain that produces both Stx1a and Stx2a was virulent in streptomycin- and ciprofloxacin-treated mice and that mice were protected by administration of an anti-Stx2 antibody. However, we discovered that in the absence of ciprofloxacin, neutralization of Stx1a enhanced the virulence of the strain, a result that corroborated our previous finding that Stx1a reduces the toxicity of Stx2a by the oral route. We further found that intraperitoneal administration of the purified Stx1a B subunit delayed the mean time to death of mice intoxicated with Stx2a and reduced the cytotoxic effect of Stx2a on Vero cells. Taken together, our data suggest that Stx1a reduces both the pathogenicity of Stx2in vivoand cytotoxicityin vitro.

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Antimicrobial Peptides Epinecidin-1 and Beta-Defesin-3 Are Effective against a Broad Spectrum of Antibiotic-Resistant Bacterial Isolates and Increase Survival Rate in Experimental Sepsis

Antibiotics ◽

10.3390/antibiotics11010076 ◽

2022 ◽

Vol 11 (1) ◽

pp. 76

Author(s):

Albert Bolatchiev

Keyword(s):

Antibacterial Activity ◽

Survival Rate ◽

Antimicrobial Peptides ◽

Lethal Dose ◽

Experimental Models ◽

Experimental Sepsis ◽

Epinephelus Coioides ◽

Sterile Saline

The antimicrobial peptides human Beta-defensin-3 (hBD-3) and Epinecidin-1 (Epi-1; by Epinephelus coioides) could be a promising tool to develop novel antibacterials to combat antibiotic resistance. The antibacterial activity of Epi-1 + vancomycin against methicillin-resistant Staphylococcus aureus (22 isolates) and Epi-1 + hBD-3 against carbapenem-resistant isolates of Klebsiella pneumoniae (n = 23), Klebsiella aerogenes (n = 17), Acinetobacter baumannii (n = 9), and Pseudomonas aeruginosa (n = 13) was studied in vitro. To evaluate the in vivo efficacy of hBD-3 and Epi-1, ICR (CD-1) mice were injected intraperitoneally with a lethal dose of K. pneumoniae or P. aeruginosa. The animals received a single injection of either sterile saline, hBD-3 monotherapy, meropenem monotherapy, hBD-3 + meropenem, or hBD-3 + Epi-1. Studied peptides showed antibacterial activity in vitro against all studied clinical isolates in a concentration of 2 to 32 mg/L. In both experimental models of murine sepsis, an increase in survival rate was seen with hBD-3 monotherapy, hBD-3 + meropenem, and hBD-3 + Epi-1. For K. pneumoniae-sepsis, hBD-3 was shown to be a promising option in overcoming the resistance of Klebsiella spp. to carbapenems, though more research is needed. In the P. aeruginosa-sepsis model, the addition of Epi-1 to hBD-3 was found to have a slightly reduced mortality rate compared to hBD-3 monotherapy.

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Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through –In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats

Scientific Reports ◽

10.1038/s41598-019-52398-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Jyoti Kaushik ◽

Simran Tandon ◽

Rishi Bhardwaj ◽

Tanzeer Kaur ◽

Surinder Kumar Singla ◽

...

Keyword(s):

Body Weight ◽

Aqueous Extract ◽

Kidney Stones ◽

Wistar Rats ◽

Lethal Dose ◽

Tribulus Terrestris ◽

Oral Toxicity ◽

Preclinical Safety

Abstract Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.

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The Immunomodulatory Effects of AlbuminIn VitroandIn Vivo

Advances in Pharmacological Sciences ◽

10.1155/2011/691928 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Derek S. Wheeler ◽

John S. Giuliano ◽

Patrick M. Lahni ◽

Alvin Denenberg ◽

Hector R. Wong ◽

...

Keyword(s):

Gene Expression ◽

Lethal Dose ◽

Intraperitoneal Administration ◽

Peritoneal Macrophages ◽

Luciferase Reporter Assay ◽

Luciferase Reporter ◽

Reporter Assay ◽

Dose Dependent

Albumin appears to have proinflammatory effectsin vitro. We hypothesized that albumin would induce a state of tolerance to subsequent administration of lipopolysaccharide (LPS)in vitroandin vivo. RAW264.7 and primary peritoneal macrophages were treated with increasing doses of bovine serum albumin (BSA) and harvested for NF-κB luciferase reporter assay or TNF-αELISA. In separate experiments, RAW264.7 cells were preconditioned with 1 mg/mL BSA for 18 h prior to LPS (10 μg/mL) treatment and harvested for NF-κB luciferase reporter assay or TNF-αELISA. Finally, C57Bl/6 mice were preconditioned with albumin via intraperitoneal administration 18 h prior to a lethal dose of LPS (60 mg/kg body wt). Blood was collected at 6 h after LPS administration for TNF-αELISA. Albumin produced a dose-dependent and TLR-4-dependent increase in NF-κB activation and TNF-αgene expressionin vitro. Albumin preconditioning abrogated the LPS-mediated increase in NF-κB activation and TNF-αgene expressionin vitroandin vivo. The clinical significance of these findings remains to be elucidated.

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A new parenteral cephalosporin. SK&F 59962: in vitro and in vivo antibacterial activity and serum levels in experimental animals.

The Journal of Antibiotics ◽

10.7164/antibiotics.28.471 ◽

1975 ◽

Vol 28 (6) ◽

pp. 471-476 ◽

Cited By ~ 6

Author(s):

PAUL ACTOR ◽

JOSEPH V. URI ◽

JOSEPH R. GUARINI ◽

IHOR ZAJAC ◽

LILLIAN PHILLIPS ◽

...

Keyword(s):

Antibacterial Activity ◽

Serum Levels ◽

Experimental Animals

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Antibacterial Activity of LCB10-0200 against Klebsiella pneumoniae

Antibiotics ◽

10.3390/antibiotics10101185 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1185

Author(s):

Sang-Hun Oh ◽

Young-Rok Kim ◽

Hee-Soo Park ◽

Kyu-Man Oh ◽

Young-Lag Cho ◽

...

Keyword(s):

Antibacterial Activity ◽

Urinary Tract ◽

Klebsiella Pneumoniae ◽

Urinary Tract Infections ◽

Antibacterial Agent ◽

In Vitro Susceptibility ◽

In Vivo Models ◽

Tract Infections

Klebsiella pneumoniae is one of the important clinical organisms that causes various infectious diseases, including urinary tract infections, necrotizing pneumonia, and surgical wound infections. The increase in the incidence of multidrug-resistance K. pneumoniae is a major problem in public healthcare. Therefore, a novel antibacterial agent is needed to treat this pathogen. Here, we studied the in vitro and in vivo activities of a novel antibiotic LCB10-0200, a siderophore-conjugated cephalosporin, against clinical isolates of K. pneumoniae. In vitro susceptibility study found that LCB10-0200 showed potent antibacterial activity against K. pneumoniae, including the beta-lactamase producing strains. The in vivo efficacy of LCB10-0200 was examined in three different mouse infection models, including systemic, thigh, and urinary tract infections. LCB10-0200 showed more potent in vivo activity than ceftazidime in the three in vivo models against the drug-susceptible and drug-resistant K. pneumoniae strains. Taken together, these results show that LCB10-0200 is a potential antibacterial agent to treat infection caused by K. pneumoniae.

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Efficacies of Sordarin Derivatives GM193663, GM211676, and GM237354 in a Murine Model of Systemic Coccidioidomycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.7.1874-1877.2000 ◽

2000 ◽

Vol 44 (7) ◽

pp. 1874-1877 ◽

Cited By ~ 21

Author(s):

Karl V. Clemons ◽

David A. Stevens

Keyword(s):

Lethal Dose ◽

Serum Levels ◽

Coccidioides Immitis ◽

Control Groups ◽

Fungal Burden ◽

Fungal Protein ◽

New Class ◽

Fungal Protein Synthesis

ABSTRACT Sordarin derivatives (Glaxo Wellcome) are a new class of compounds that selectively inhibit fungal protein synthesis and have a broad spectrum of activity. Systemic coccidioidomycosis was established in female CD-1 mice infected with Coccidioides immitis, and therapy was begun on day 4 with either GM193663, GM211676, GM237354, fluconazole, or no treatment; compounds were given twice daily orally for 19 days at 20 or 100 mg/kg/day. The serum pharmacokinetics of the compounds were studied in uninfected mice. The MICs of GM193663, GM211676, and GM237354 for C. immitis were 1.56, 0.39, and 0.39 μg/ml, respectively, and the minimum fungicidal concentrations were 6.25, 3.13, and 0.39 μg/ml, respectively. Peak serum levels (sampled at 1 to 2 h) after a single 50-mg/kg dose were 9.8 μg/ml for GM193663, 13 μg/ml for GM211676, and 6.0 μg/ml for GM237354. No accumulation occurred after 19 days of dosing, and peak levels were lower at 3.2 μg/ml for GM193663, 4.0 μg/ml for GM211676, and <2.5 μg/ml for GM237354. We estimate that thet 1/2 for each compound in serum is <2 h. In vivo, all compounds showed dose-responsive efficacy, significantly prolonging survival over the control groups (100% lethal dose); 80 to 100% of the mice given the 100-mg/kg doses of fluconazole or a GM drug survived. All 100-mg/kg/day regimens were equivalent. At 20 mg/kg/day, GM211676 was equivalent to 100 mg of fluconazole/kg/day, indicating that GM211676 was ∼5-fold more efficacious. No mice surviving the 49 days of the experiment were free of infection. All drugs dose responsively reduced the fungal burden in the spleen, liver, and lungs, and GM237354 at 100 mg/kg/day was superior to all of the other regimens in the reduction of burden in all organs. C. immitis was susceptible both in vitro and in vivo to the GM compounds, which were found to be equivalent or superior to fluconazole. These results are encouraging, indicating that further testing in other models of fungal disease is warranted.

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Antibacterial Activity of a Promising Antibacterial Agent: 22-(4-(2-(4-Nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin

Molecules ◽

10.3390/molecules26123502 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3502

Author(s):

Xiang-Yi Zuo ◽

Hong Gao ◽

Mei-Ling Gao ◽

Zhen Jin ◽

You-Zhi Tang

Keyword(s):

Antibacterial Activity ◽

Galleria Mellonella ◽

Systemic Infection ◽

Effect Study ◽

Infection Model ◽

Oral Toxicity ◽

Reference Drug ◽

Antibiotic Effect

A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED50) of NPDM in a Galleria mellonella infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.

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IN VITRO AND IN VIVO TOXICITY EVALUATION OF TRAPA BISPINOSA ROXB. STARCH

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021.v13s1.y0109 ◽

2021 ◽

pp. 58-62

Author(s):

SURADWADEE THUNGMUNGMEE ◽

NAKUNTWALAI WISIDSRI

Keyword(s):

Lethal Dose ◽

Clinical Signs ◽

Fibroblast Cell ◽

In Vivo Studies ◽

Oral Toxicity ◽

Cosmetic Ingredients ◽

Nih 3T3 ◽

Fibroblast Cell Lines

Objective: This study aimed to assess the toxicity of Trapa bispinosa Roxb. starch (TBS) through in vitro and in vivo studies.Methods: The cytotoxicity of TBS extract (TBSE) was evaluated on RAW 264.7 macrophage and NIH 3T3 fibroblast cell lines and the acute dermal andoral toxicities of TBS were analyzed in rats. To access acute dermal toxicity, the rats received a single application of 200, 1000, and 2000 mg/kg BW ofTBS, while for acute oral toxicity, the rats received a single administration of 300 and 2000 mg/kg BW of TBS. All animals were observed for changesin body weight, mortality, and clinical signs of abnormality after application and administration of the TBS.Results: The in vitro results showed that TBSE at concentrations of 6.25–200 μg/ml was non-cytotoxic to macrophages and fibroblasts. From acutetoxicity studies, the lethal dose of TBS was considered to be over 2000 mg/kg BW. No mortality, clinical signs of abnormality, or gross pathology weredetected at necropsy.Conclusion: TBS is non-toxic in in vitro and in vivo studies. Therefore, TBS can be used as pharmaceuticals excipients or cosmetic ingredients.

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In Vivo and In Vitro Toxicity Profiles of Hexane Extract of Alpinia malaccensis Rhizome in Rat and Cell Line Models

Journal of Toxicology ◽

10.1155/2021/9578474 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

T. Somarathna ◽

M. G. Thammitiyagodage ◽

K. K. D. S. Ranaweera ◽

G. A. S. Premakumara ◽

M. A. Akbarsha ◽

...

Keyword(s):

Body Weight ◽

Biochemical Parameters ◽

Lethal Dose ◽

In Vitro Cytotoxicity ◽

Hexane Extract ◽

Acute Oral Toxicity ◽

Oral Toxicity ◽

Hematological And Biochemical Parameters

The objective of the study was to evaluate the potential toxicity of crude n-hexane extract of Alpinia malaccensis rhizome. The in vivo acute oral toxicity was evaluated by administering a single oral dose of the extract at 0, 300, or 2000 mg/kg body weight to female Wistar rats according to modified OECD Test Guideline 423. For the in vitro cytotoxicity study, A549, HepG2, 3T3, and COS-7 cell lines were exposed to different doses of A. malaccensis extract and cell viability was assessed adopting MTT assay followed by AO/EB staining, Hoechst staining, and comet assay with a view to compare the cellular and molecular mechanisms underlying the toxicity, if any. It was found that administration of 2000 mg/kg bw dose in in vivo oral acute toxicity study did not produce significant toxicity or mortality. No significant ( p < 0.05 ) differences were observed for body weight and hematological and biochemical parameters compared to control after 14 days of treatment. No changes in behavior, body weight, hematological and biochemical parameters, and aspects of histopathology were observed when compared to the control. Thus, the possible oral lethal dose for A. malaccensis extract is above 2000 mg/kg body weight. The in vitro cytotoxicity analysis showed nontoxicity concentrations of the extract to be 2, 1.4, 30, and 1.4 µg/mL for A549, HepG2, 3T3, and COS-7 cells, respectively, where no apoptotic/necrotic cell death and DNA damage were observed. In conclusion, the extract of rhizome of A. malaccensis did not produce apparent cytotoxicity or acute oral toxicity, confirming the scope to use A. malaccensis as a safe food preservative and a natural therapeutic product after further subacute and chronic toxicity studies.

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