In vitro and in vivo bactericidal activity of Vitex negundo leaf extract against diverse multidrug resistant enteric bacterial pathogens

ABSTRACT PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (μg/ml) for PD 0305970 capable of inhibiting ≥90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were >100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50 = 3.2 mg/kg) and was 22-fold more potent than levofloxacin.

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In VitroandIn VivoActivities of E-101 Solution against Acinetobacter baumannii Isolates from U.S. Military Personnel

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01606-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3603-3608 ◽

Cited By ~ 4

Author(s):

G. A. Denys ◽

J. C. Davis ◽

P. D. O'Hanley ◽

J. T. Stephens

Keyword(s):

Acinetobacter Baumannii ◽

Bactericidal Activity ◽

Military Personnel ◽

Multidrug Resistant ◽

Full Thickness ◽

Content Type ◽

Full Thickness Excision ◽

Time Kill

ABSTRACTWe evaluated thein vitroandin vivoactivity of a novel topical myeloperoxidase-mediated antimicrobial, E-101 solution, against 5 multidrug-resistantAcinetobacter baumanniiisolates recovered from wounded American soldiers. Time-kill studies demonstrated rapid bactericidal activity against allA. baumanniistrains tested in the presence of 3% blood. Thein vitrobactericidal activity of E-101 solution againstA. baumanniistrains was confirmed in a full-thickness excision rat model. Additionalin vivostudies appear warranted.

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Efficacy of the New Lantibiotic NAI-107 in Experimental Infections Induced by Multidrug-Resistant Gram-Positive Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01288-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1671-1676 ◽

Cited By ~ 85

Author(s):

Daniela Jabés ◽

Cristina Brunati ◽

GianPaolo Candiani ◽

Simona Riva ◽

Gabriella Romanó ◽

...

Keyword(s):

Bactericidal Activity ◽

Bacterial Load ◽

Severe Infection ◽

Multidrug Resistant ◽

Minimal Bactericidal Concentration ◽

Gram Positive ◽

Immunocompetent Mice ◽

Dose Proportional

ABSTRACTNAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus(MRSA), glycopeptide-intermediateS. aureus(GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate thein vivoefficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediateStreptococcus pneumoniaestrain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED50) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). Inthe granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log10-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observedin vitrowas thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

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Histatin-Derived Monomeric and Dimeric Synthetic Peptides Show Strong Bactericidal Activity towards Multidrug-Resistant Staphylococcus aureus In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00196-07 ◽

2007 ◽

Vol 51 (9) ◽

pp. 3416-3419 ◽

Cited By ~ 24

Author(s):

Mick M. Welling ◽

Carlo P. J. M. Brouwer ◽

Wim van ′t Hof ◽

Enno C. I. Veerman ◽

Arie V. Nieuw Amerongen

Keyword(s):

Staphylococcus Aureus ◽

Soft Tissue ◽

Bactericidal Activity ◽

Synthetic Peptides ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Drug Resistant ◽

Drug Resistant Bacteria

ABSTRACT Homodimerization of histatin-derived peptides generally led to improved bactericidal activity against Staphylococcus aureus in vitro. In vivo, monomers and dimers were equally active in killing bacteria in mice with a soft tissue infection. Altogether, these peptides are promising compounds for the development of novel therapeutics against infections with drug-resistant bacteria.

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Perforin-2 Permeabilizes the Envelope of Phagocytosed Bacteria

10.1101/274878 ◽

2018 ◽

Author(s):

Fangfang Bai ◽

Ryan M. McCormack ◽

Suzanne Hower ◽

Gregory V. Plano ◽

Mathias G. Lichtenheld ◽

...

Keyword(s):

Salmonella Typhimurium ◽

Surface Antigen ◽

Bactericidal Activity ◽

Bacterial Pathogens ◽

Intracellular Pathogen ◽

Wild Type

AbstractPerforin-2, the product of the MPEG1 gene, limits the spread and dissemination of bacterial pathogens in vivo. It is highly expressed in murine and human phagocytes, and macrophages lacking Perforin-2 are compromised in their ability to kill phagocytosed bacteria. In this study we used Salmonella typhimurium as a model intracellular pathogen to elucidate the mechanism of Perforin-2‘s bactericidal activity. In vitro Perforin-2 was found to facilitate the degradation of antigens contained within the envelope of phagocytosed bacteria. In contrast, degradation of a representative surface antigen was found to be independent of Perforin-2. Consistent with our in vitro results a protease sensitive, periplasmic superoxide disumutase (SodCII) contributed to the virulence of S. typhimurium in Perforin-2 knockout but not wild-type mice. In aggregate our studies indicate that Perforin-2 breaches the envelope of phagocytosed bacteria facilitating the delivery of proteases and other antimicrobial effectors to sites within the bacterial envelope.

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Effects of Probiotics in the Management of Infected Chronic Wounds: From Cell Culture to Human Studies

Current Clinical Pharmacology ◽

10.2174/1574884714666191111130630 ◽

2020 ◽

Vol 15 (3) ◽

pp. 193-206

Author(s):

Brognara Lorenzo ◽

Salmaso Luca ◽

Mazzotti Antonio ◽

Di M. Alberto ◽

Faldini Cesare ◽

...

Keyword(s):

Chronic Wounds ◽

Animal Experiments ◽

Multidrug Resistant ◽

Preliminary Evidence ◽

Human Studies ◽

In Vivo Studies ◽

Resistant Bacteria ◽

Keywords Probiotics

Background: Chronic wounds are commonly associated with polymicrobial biofilm infections. In the last years, the extensive use of antibiotics has generated several antibiotic-resistant variants. To overcome this issue, alternative natural treatments have been proposed, including the use of microorganisms like probiotics. The aim of this manuscript was to review current literature concerning the application of probiotics for the treatment of infected chronic wounds. Methods: Relevant articles were searched in the Medline database using PubMed and Scholar, using the keywords “probiotics” and “wound” and “injuries”, “probiotics” and “wound” and “ulcer”, “biofilm” and “probiotics” and “wound”, “biofilm” and “ulcer” and “probiotics”, “biofilm” and “ulcer” and “probiotics”, “probiotics” and “wound”. Results: The research initially included 253 articles. After removal of duplicate studies, and selection according to specific inclusion and exclusion criteria, 19 research articles were included and reviewed, accounting for 12 in vitro, 8 in vivo studies and 2 human studies (three articles dealing with animal experiments included also in vitro testing). Most of the published studies about the effects of probiotics for the treatment of infected chronic wounds reported a partial inhibition of microbial growth, biofilm formation and quorum sensing. Discussion: The application of probiotics represents an intriguing option in the treatment of infected chronic wounds with multidrug-resistant bacteria; however, current results are difficult to compare due to the heterogeneity in methodology, laboratory techniques, and applied clinical protocols. Lactobacillus plantarum currently represents the most studied strain, showing a positive application in burns compared to guideline treatments, and an additional mean in chronic wound infections. Conclusions: Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings such as infected chronic wounds, large, long-term clinical trials are still lacking, and further research is needed.

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Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms22052530 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2530

Author(s):

Bijean D. Ford ◽

Diego Moncada Giraldo ◽

Camilla Margaroli ◽

Vincent D. Giacalone ◽

Milton R. Brown ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bactericidal Activity ◽

Scavenger Receptor ◽

Receptor Expression ◽

Blood Monocytes ◽

Bacterial Killing ◽

Blood Neutrophils ◽

Vitro Model

Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection.

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Silver Nanoparticles and Their Antibacterial Applications

International Journal of Molecular Sciences ◽

10.3390/ijms22137202 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7202

Author(s):

Tamara Bruna ◽

Francisca Maldonado-Bravo ◽

Paul Jara ◽

Nelson Caro

Keyword(s):

Silver Nanoparticles ◽

Antibacterial Agents ◽

Multidrug Resistant ◽

Secondary Effects ◽

Cytotoxic Effects ◽

Factors Affecting ◽

Gram Positive Bacteria ◽

Resistant Strains

Silver nanoparticles (AgNPs) have been imposed as an excellent antimicrobial agent being able to combat bacteria in vitro and in vivo causing infections. The antibacterial capacity of AgNPs covers Gram-negative and Gram-positive bacteria, including multidrug resistant strains. AgNPs exhibit multiple and simultaneous mechanisms of action and in combination with antibacterial agents as organic compounds or antibiotics it has shown synergistic effect against pathogens bacteria such as Escherichia coli and Staphylococcus aureus. The characteristics of silver nanoparticles make them suitable for their application in medical and healthcare products where they may treat infections or prevent them efficiently. With the urgent need for new efficient antibacterial agents, this review aims to establish factors affecting antibacterial and cytotoxic effects of silver nanoparticles, as well as to expose the advantages of using AgNPs as new antibacterial agents in combination with antibiotic, which will reduce the dosage needed and prevent secondary effects associated to both.

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A molecular architectural design that promises potent antimicrobial activity against multidrug-resistant pathogens

NPG Asia Materials ◽

10.1038/s41427-021-00287-y ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Bing Yuan ◽

Jiaojiao Liu ◽

Zhixiong Deng ◽

Lin Wei ◽

Wenwen Li ◽

...

Keyword(s):

Architectural Design ◽

Building Blocks ◽

Multidrug Resistant ◽

In Vitro Cytotoxicity ◽

Antimicrobial Drugs ◽

Minimal Inhibitory Concentrations ◽

Antimicrobial Efficiency ◽

Multidrug Resistant Pathogens

AbstractAddressing the devastating threat of drug-resistant pathogens requires the discovery of new antibiotics with advanced action mechanisms and/or novel strategies for drug design. Herein, from a biophysical perspective, we design a class of synthetic antibacterial complexes with specialized architectures based on melittin (Mel), a natural antimicrobial peptide, and poly(ethylene glycol) (PEG), a clinically available agent, as building blocks that show potent and architecture-modulated antibacterial activity. Among the complexes, the flexibly linear complex consisting of one Mel terminally connected with a long-chained PEG (e.g., PEG12k–1*Mel) shows the most pronounced improvement in performance compared with pristine Mel, with up to 500% improvement in antimicrobial efficiency, excellent in vitro activity against multidrug-resistant pathogens (over a range of minimal inhibitory concentrations of 2–32 µg mL−1), a 68% decrease in in vitro cytotoxicity, and a 57% decrease in in vivo acute toxicity. A lipid-specific mode of action in membrane recognition and an accelerated “channel” effect in perforating the bacterial membrane of the complex are described. Our results introduce a new way to design highly efficient and low-toxicity antimicrobial drugs based on architectural modulations with clinically available agents.

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