scholarly journals A Silkworm Infection Model for In Vivo Study of Glycopeptide Antibiotics

Antibiotics ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 300
Author(s):  
Aurora Montali ◽  
Francesca Berini ◽  
Maurizio Francesco Brivio ◽  
Maristella Mastore ◽  
Alessio Saviane ◽  
...  
Keyword(s):  
First Generation ◽  
Bacterial Load ◽  
Larval Survival ◽  
Infection Model ◽  
Glycopeptide Antibiotics ◽  
Cell Wall Assembly ◽  
Aureus Infection ◽  
Peptide Expression ◽  
Antimicrobial Peptide Expression

Glycopeptide antibiotics (GPAs) are drugs of last resort for treating infections by Gram-positive bacteria. They inhibit bacterial cell wall assembly by binding to the d-Ala-d-Ala terminus of peptidoglycan precursors, leading to cell lysis. Vancomycin and teicoplanin are first generation GPAs, while dalbavancin is one of the few, recently approved, second generation GPAs. In this paper, we developed an in vivo insect model to compare, for the first time, the efficacy of these three GPAs in curing Staphylococcus aureus infection. Differently from previous reports, Bombyx mori larvae were reared at 37 °C, and the course of infection was monitored, following not only larval survival, but also bacterial load in the insect body, hemocyte activity, phenoloxidase activity, and antimicrobial peptide expression. We demonstrated that the injection of S. aureus into the hemolymph of B. mori larvae led to a marked reduction of their survival rate within 24–48 h. GPAs were not toxic to the larvae and cured S. aureus infection. Dalbavancin was more effective than first generation GPAs. Due to its great advantages (i.e., easy and safe handling, low rearing costs, low antibiotic amount needed for the tests, no restrictions imposed by ethical and regulatory issues), this silkworm infection model could be introduced in preclinical phases—prior to the use of mice—accelerating the discovery/development rate of novel GPAs.

scholarly journals Staphylococcus aureus Infection of Epidermal Keratinocytes Promotes Expression of Innate Antimicrobial Peptides

2005 ◽  
Vol 73 (8) ◽  
pp. 5241-5244 ◽  
Author(s):  
Barbara E. Menzies ◽  
Aimee Kenoyer
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptides ◽  
Antimicrobial Peptide ◽  
Human Keratinocytes ◽  
Lipoteichoic Acid ◽  
Epidermal Keratinocytes ◽  
Aureus Infection ◽  
Inflammatory Stimuli ◽  
Peptide Expression ◽  
Antimicrobial Peptide Expression

ABSTRACT Keratinocytes upregulate expression of endogenous antimicrobial peptides in response to inflammatory stimuli. We show that both viable and heat-inactivated Staphylococcus aureus and lipoteichoic acid differentially alter expression of these peptides upon contact with human keratinocytes. The findings indicate a diversity of staphylococcal factors involved in upregulation of antimicrobial peptide expression in cutaneous epithelia.

scholarly journals Systemic Antibacterial Activity of Novel Synthetic Cyclic Peptides

2005 ◽  
Vol 49 (8) ◽  
pp. 3302-3310 ◽  
Author(s):  
Véronique Dartois ◽  
Jorge Sanchez-Quesada ◽  
Edelmira Cabezas ◽  
Ellen Chi ◽  
Chad Dubbelde ◽  
...  
Keyword(s):  
Cyclic Peptides ◽  
Prolonged Exposure ◽  
Cyclic Peptide ◽  
Present Report ◽  
Bacterial Load ◽  
Pharmacokinetic Profile ◽  
Therapeutic Window ◽  
Infection Model

ABSTRACT Cyclic peptides with an even number of alternating d,l-α-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 μg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-α-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.

scholarly journals Comparative Efficacies of Human Simulated Exposures of Telavancin and Vancomycin against Methicillin-Resistant Staphylococcus aureus with a Range of Vancomycin MICs in a Murine Pneumonia Model

2010 ◽  
Vol 54 (12) ◽  
pp. 5115-5119 ◽  
Author(s):  
Jared L. Crandon ◽  
Joseph L. Kuti ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Load ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Methicillin Resistant ◽  
Vancomycin Mics ◽  
Mrsa Strains

ABSTRACT Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log10 CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

scholarly journals Comparative Effects of Carbapenems on Bacterial Load and Host Immune Response in aKlebsiella pneumoniaeMurine Pneumonia Model

2010 ◽  
Vol 55 (2) ◽  
pp. 836-844 ◽  
Author(s):  
Jamese J. Hilliard ◽  
John L. Melton ◽  
LeRoy Hall ◽  
Darren Abbanat ◽  
Jeffrey Fernandez ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Infection Model ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Tissue Sections ◽  
Time Period ◽  
Infection Treatment ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

ABSTRACTDoripenem is a carbapenem with potent broad-spectrum activity against Gram-negative pathogens, including antibiotic-resistantEnterobacteriaceae. As the incidence of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli is increasing, it was of interest to examine thein vivocomparative efficacy of doripenem, imipenem, and meropenem against aKlebsiella pneumoniaeisolate expressing the TEM-26 ESBL enzyme. In a murine lethal lower respiratory infection model, doripenem reduced theKlebsiellalung burden by 2 log10CFU/g lung tissue over the first 48 h of the infection. Treatment of mice with meropenem or imipenem yielded reductions of approximately 1.5 log10CFU/g during this time period. Seven days postinfection,Klebsiellatiters in the lungs of treated mice decreased an additional 2 log10CFU/g relative to those in the lungs of untreated control animals. Lipopolysaccharide (LPS) endotoxin release assays indicated that 6 h postinfection, meropenem- and imipenem-treated animals had 10-fold more endotoxin in lung homogenates and sera than doripenem-treated mice. Following doripenem treatment, the maximum endotoxin release postinfection (6 h) was 53,000 endotoxin units (EU)/ml, which was 2.7- and 6-fold lower than imipenem or meropenem-treated animals, respectively. While the levels of several proinflammatory cytokines increased in both the lungs and sera following intranasalK. pneumoniaeinoculation, doripenem treatment, but not meropenem or imipenem treatment, resulted in significantly increased interleukin 6 levels in lung homogenates relative to those in lung homogenates of untreated controls, which may contribute to enhanced neutrophil killing of bacteria in the lung. Histological examination of tissue sections indicated less overall inflammation and tissue damage in doripenem-treated mice, consistent with improved antibacterial efficacy, reduced LPS endotoxin release, and the observed cytokine induction profile.

scholarly journals In Vivo Activity of Ceftobiprole in Murine Skin Infections Due to Staphylococcus aureus and Pseudomonas aeruginosa

2009 ◽  
Vol 54 (1) ◽  
pp. 116-125 ◽  
Author(s):  
Jeffrey Fernandez ◽  
Jamese J. Hilliard ◽  
Darren Abbanat ◽  
Wenyan Zhang ◽  
John L. Melton ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Load ◽  
Lesion Size ◽  
Infection Model ◽  
Lesion Volume ◽  
Infection Models ◽  
Mrsa Infection ◽  
Response Profiles

ABSTRACT Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC β-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC β-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC β-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

scholarly journals Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

2005 ◽  
Vol 49 (6) ◽  
pp. 2294-2301 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
Christine M. Johnson ◽  
Diane K. Driscoll ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Significant Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Long Term Treatment

ABSTRACT This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

scholarly journals Contribution of swarming motility to dissemination in a Pseudomonas aeruginosa murine skin abscess infection model

2020 ◽  
Author(s):  
Shannon R Coleman ◽  
Daniel Pletzer ◽  
Robert E W Hancock
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Bacterial Load ◽  
Infection Model ◽  
Swarming Motility ◽  
Semisolid Medium ◽  
Low Concentrations ◽  
Complex Adaptive

Abstract Swarming motility in Pseudomonas aeruginosa is a multicellular adaptation induced by semisolid medium with amino acids as a nitrogen source. By phenotypic screening, we differentiated swarming from other complex adaptive phenotypes, such as biofilm formation, swimming and twitching, by identifying a swarming-specific mutant in ptsP, a metabolic regulator. This swarming-deficient mutant was tested in an acute murine skin abscess infection model. Bacteria were recovered at significantly lower numbers from organs of mice infected with the ∆ptsP mutant. We also tested the synthetic peptide 1018 for activity against different motilities and efficacy in vivo. Treatment with 1018 mimicked the phenotype of the ∆ptsP mutant in vitro, as swarming was inhibited at low concentrations (&lt;2 μg/mL) but not swimming or twitching, and in vivo, as mice had a reduced bacterial load recovered from organs. Therefore, PtsP functions as a regulator of swarming, which in turn contributes to dissemination and colonization in vivo.

scholarly journals An Improved Small-Molecule Inhibitor of FtsZ with SuperiorIn VitroPotency, Drug-Like Properties, andIn VivoEfficacy

2012 ◽  
Vol 57 (1) ◽  
pp. 317-325 ◽  
Author(s):  
Neil R. Stokes ◽  
Nicola Baker ◽  
James M. Bennett ◽  
Joanne Berry ◽  
Ian Collins ◽  
...  
Keyword(s):  
Small Molecule ◽  
Bacterial Load ◽  
Drug Candidate ◽  
Infection Model ◽  
Antibacterial Drug ◽  
Content Type ◽  
Intravenous And Oral Administration ◽  
Derivatives Of

ABSTRACTThe bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. Thein vitroandin vivocharacterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 μg/ml against all staphylococcal species, including methicillin- and multidrug-resistantStaphylococcus aureusandStaphylococcus epidermidis. Compound 1 inhibited anS. aureusstrain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitablein vitropharmaceutical properties and a favorablein vivopharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemicS. aureusinfection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number ofS. aureuscells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.

scholarly journals IFN-γ-/- mice resist Actinobacillus pleuropneumoniae infection by promoting early lung IL-18 release and PMN-I accumulation

2021 ◽  
Author(s):  
Chuntong Bao ◽  
Baijun Liu ◽  
Rining Zhu ◽  
Jiameng Xiao ◽  
Ziheng Li ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Bacterial Load ◽  
Actinobacillus Pleuropneumoniae ◽  
Infection Model ◽  
Treatment Protocols ◽  
Porcine Pleuropneumonia ◽  
Mouse Infection Model ◽  
Common Infectious Disease ◽  
Ifn Γ

Porcine pleuropneumonia is a common infectious disease of pigs caused by Actinobacillus pleuropneumoniae (APP). IFN-γ expression increases in the lung of pigs after APP infection, but the role of IFN-γ during the infection is still obscure. In this study, an IFN-γ-/- mouse infection model was established, and bacterial load, the levels of inflammatory cytokines and the types of neutrophils in the lungs were studied at different times post APP infection. We found that wild-type (WT) mice were more susceptible to APP than IFN-γ-/- mice. At 6 h post infection (hpi), the expression of IL-18 and IL-1β in the lungs of IFN-γ-/- mice were significantly increased compared to WT mice. The bacterial load and levels of inflammatory cytokines (IL-1β and IL-6) of IFN-γ-/- mice were significantly reduced at 12 hpi compared to WT mice. After an initial loss, the numbers of lung polymorphonuclear (PMN)-I cells dramatically increased in the lungs of IFN-γ-/- but not WT mice, whereas PMN-II cells continually decreased. Finally, in vivo administration of IL-18 significantly reduced clinical scores and bacterial load in the lungs of APP-infected mice. This study identifies IFN-γ as a target for regulating the inflammatory response in the lung, and provides a basis for understanding the course of clinical bacterial pneumonia and for the formulation of treatment protocols.

scholarly journals Cinnamomum cassia and Syzygium aromaticum Essential Oils Reduce the Colonization of Salmonella Typhimurium in an In Vivo Infection Model Using Caenorhabditis elegans

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5598
Author(s):  
Marie Lang ◽  
Aude Montjarret ◽  
Emmanuel Duteil ◽  
Gilles Bedoux
Keyword(s):  
Caenorhabditis Elegans ◽  
Essential Oils ◽  
Salmonella Typhimurium ◽  
Bacterial Colonization ◽  
Bacterial Load ◽  
Infection Model ◽  
Syzygium Aromaticum ◽  
Cinnamomum Cassia ◽  
C Elegans

The regulation of intestinal colonization in livestock by means of non-bactericidal additives is an important management lever for zoonotic bacteria such as Salmonella spp. Caenorhabditis elegans is proposed here as a model for the evaluation of five essential oils (EOs) as anti-colonization products against Salmonella Typhimurium. An evaluation of the toxicity of EOs for C. elegans showed LD50 values ranging from 74.5 ± 9.6 µg/mL for Cinnamomum cassia (CEO) to 271.6 ± 14.9 µg/mL for Syzygium aromaticum (SyEO). Both EOs significantly inhibited bacterial colonization in the digestive tract of C. elegans with reductions of 0.88 and 0.70 log CFU/nematode at nontoxic concentrations of 50 µg/mL and 150 µg/mL, respectively. With the minimal bactericidal concentrations of CEO and SyEO against S. Typhimurium being 312.5 µg/mL and 625 µg/mL, respectively, an antibacterial effect can be excluded to explain the inhibition of the bacterial load. The anti-colonizing activity of these two EOs could, however, be related to an inhibition of the swimming motility, which was significantly reduced by 23.47% for CEO at 50 µg/mL and 19.56% for SyEO at 150 µg/mL. This study shows the potential of C. elegans as a predictive in vivo model of anti-colonizing activities that is suitable for the evaluation of essential oils.

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