Integrated endotoxin-adsorption and antibacterial properties of platelet-membrane-coated copper silicate hollow microspheres for wound healing

AbstractSerious infection caused by drug-resistant gram-negative bacteria and their secreted toxins (e.g., lipopolysaccharide) is a serious threat to human health. Thus, treatment strategies that efficiently kill bacteria and reducing the impact of their toxins simultaneously are urgently required. Herein, a novel antibacterial platform composed of a mesoporous copper silicate microsphere (CSO) core and a platelet membrane (PM) shell was prepared (CSO@PM). CSO@PM specifically targets bacteria owing to formyl peptide receptors on the PM and, combined with photothermal therapy (PTT), exhibits highly effective bacter icidal activity. Importantly, CSO@PM can adsorb lipopolysaccharide secreted by gram-negative bacteria, resulting in inflammation reduction. Thus, CSO@PM stimulates re-epithelialization and granulation-tissue formation, promoting wound healing. Moreover, this antibacterial platform exhibits no obvious toxicity at all the test concentrations in vitro and in vivo. Thus, CSO@PM exhibits a robust antibacterial effect and a strong toxin-adsorption capacity, facilitating the clinical treatment of many bacterial infections and the development of next-generation antibacterial nanoagents. Graphical Abstract

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Integrated Endotoxin-Adsorption and Antibacterial Properties of Platelet-Membrane-Coated Copper Silicate Hollow Microspheres for Wound Healing

10.21203/rs.3.rs-903043/v1 ◽

2021 ◽

Author(s):

Zaihui Peng ◽

Xiaochun Zhang ◽

Long Yuan ◽

Yajie Chen ◽

Ting Li ◽

...

Keyword(s):

Wound Healing ◽

Bacterial Infections ◽

Antibacterial Properties ◽

Platelet Membrane ◽

Gram Negative Bacteria ◽

Gram Negative ◽

The Impact ◽

Copper Silicate

Abstract Serious infection caused by drug-resistant gram-negative bacteria and their secreted toxins (e.g., lipopolysaccharide) is a serious threat to human health. Thus, treatment strategies that efficiently kill bacteria and reducing the impact of their toxins simultaneously are urgently required. Herein, a novel antibacterial platform composed of a mesoporous copper silicate microsphere (CSO) core and a platelet membrane (PM) shell was prepared (CSO@PM). CSO@PM specifically targets bacteria owing to formyl peptide receptors on the PM and, combined with photothermal therapy (PTT), exhibits highly effective bactericidal activity. Importantly, CSO@PM can adsorb lipopolysaccharide secreted by gram-negative bacteria, resulting in inflammation reduction. Thus, CSO@PM stimulates re-epithelialization and granulation-tissue formation, promoting wound healing. Moreover, this antibacterial platform exhibits no obvious toxicity at all the test concentrations in vitro and in vivo. Thus, CSO@PM exhibits a robust antibacterial effect and a strong toxin-adsorption capacity, facilitating the clinical treatment of many bacterial infections and the development of next-generation antibacterial nanoagents.

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Visualizing the Potential Impairment of Polymyxin B to Central Nervous System Through MR Susceptibility-Weighted Imaging

Frontiers in Pharmacology ◽

10.3389/fphar.2021.784864 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ni Zhang ◽

Lichong Zhu ◽

Qiuhong Ouyang ◽

Saisai Yue ◽

Yichun Huang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Polymyxin B ◽

Susceptibility Weighted Imaging ◽

Gram Negative Bacteria ◽

Severe Toxicity ◽

Gram Negative ◽

The Impact

Polymyxin B (PMB) exert bactericidal effects on the cell wall of Gram-negative bacteria, leading to changes in the permeability of the cytoplasmic membrane and resulting in cell death, which is sensitive to the multi-resistant Gram-negative bacteria. However, the severe toxicity and adverse side effects largely hamper the clinical application of PMB. Although the molecular pathology of PMB neurotoxicity has been adequately studied at the cellular and molecular level. However, the impact of PMB on the physiological states of central nervous system in vivo may be quite different from that in vitro, which need to be further studied. Therefore, in the current study, the biocompatible ultra-uniform Fe3O4 nanoparticles were employed for noninvasively in vivo visualizing the potential impairment of PMB to the central nervous system. Systematic studies clearly reveal that the prepared Fe3O4 nanoparticles can serve as an appropriate magnetic resonance contrast agent with high transverse relaxivity and outstanding biosafety, which thus enables the following in vivo susceptibility-weighted imaging (SWI) studies on the PMB-treated mice models. As a result, it is first found that the blood-brain barrier (BBB) of mice may be impaired by successive PMB administration, displaying by the discrete punctate SWI signals distributed asymmetrically across brain regions in brain parenchyma. This result may pave a noninvasive approach for in-depth studies of PMB medication strategy, monitoring the BBB changes during PMB treatment, and even assessing the risk after PMB successive medication in multidrug-resistant Gram-negative bacterial infected patients from the perspective of medical imaging.

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Multiple Mechanisms of the Synthesized Antimicrobial Peptide TS against Gram-Negative Bacteria for High Efficacy Antibacterial Action In Vivo

Molecules ◽

10.3390/molecules26010060 ◽

2020 ◽

Vol 26 (1) ◽

pp. 60

Author(s):

Rui Zhang ◽

Xiaobo Fan ◽

Xinglu Jiang ◽

Mingyuan Zou ◽

Han Xiao ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Bacterial Infections ◽

Bacterial Resistance ◽

Divalent Cations ◽

Resistant Bacteria ◽

Antibacterial Drug ◽

Gram Negative Bacteria ◽

Gram Negative

The emergence of drug-resistant bacteria emphasizes the urgent need for novel antibiotics. The antimicrobial peptide TS shows extensive antibacterial activity in vitro and in vivo, especially in gram-negative bacteria; however, its antibacterial mechanism is unclear. Here, we find that TS without hemolytic activity disrupts the integrity of the outer bacterial cell membrane by displacing divalent cations and competitively binding lipopolysaccharides. In addition, the antimicrobial peptide TS can inhibit and kill E. coli by disintegrating the bacteria from within by interacting with bacterial DNA. Thus, antimicrobial peptide TS’s multiple antibacterial mechanisms may not easily induce bacterial resistance, suggesting use as an antibacterial drug to be for combating bacterial infections in the future.

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In Vitro and In Vivo Activities of Novel 2-(Thiazol-2-ylthio)-1β-Methylcarbapenems with Potent Activities against Multiresistant Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.8.2471-2480.2003 ◽

2003 ◽

Vol 47 (8) ◽

pp. 2471-2480 ◽

Cited By ~ 20

Author(s):

Yutaka Ueda ◽

Makoto Sunagawa

Keyword(s):

Bactericidal Activity ◽

Bacterial Infections ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative ◽

Log Reduction ◽

Highly Active ◽

Time Kill

ABSTRACT SM-197436, SM-232721, and SM-232724 are new 1β-methylcarbapenems with a unique 4-substituted thiazol-2-ylthio moiety at the C-2 side chain. In agar dilution susceptibility testing these novel carbapenems were active against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) with a MIC90 of ≤4 μg/ml. Furthermore, SM-232724 showed strong bactericidal activity against MRSA, in contrast to linezolid, which was bacteriostatic up to four times the MIC. SM-232724 showed good therapeutic efficacy comparable to those of vancomycin and linezolid against systemic infections of MRSA in cyclophosphamide-treated mice. The MICs of SM-197436, SM-232721, and SM-232724 for streptococci, including penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae strains, ranged from ≤0.063 to 0.5 μg/ml. These drugs were the most active β-lactams tested against Enterococcus faecium, and the MIC90 s for ampicillin-resistant E. faecium ranged between 8 and 16 μg/ml, which were slightly higher than the value for linezolid. However, time-kill assays revealed the superior bactericidal activity of SM-232724 compared to those of quinupristin-dalfopristin and linezolid against an E. faecium strain with a 4-log reduction in CFU at four times the MIC after 24 h of exposure to antibiotics. In addition, SM-232724 significantly reduced the numbers of bacteria in a murine abscess model with the E. faecium strain: its efficacy was superior to that of linezolid, although the MICs (2 μg/ml) of these two agents are the same. Among gram-negative bacteria, these three carbapenems were highly active against Haemophilus influenzae (including ampicillin-resistant strains), Moraxella catarrhalis, and Bacteroides fragilis, and showed antibacterial activity equivalent to that of imipenem for Escherichia coli, Klebsiella pneumoniae, and Proteus spp. Thus, these new carbapenems are promising candidates for agents to treat nosocomial bacterial infections by gram-positive and gram-negative bacteria, especially multiresistant gram-positive cocci, including MRSA and vancomycin-resistant enterococci.

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Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666191223110518 ◽

2020 ◽

Vol 20 (3) ◽

pp. 192-208 ◽

Cited By ~ 1

Author(s):

Talita Odriane Custodio Leite ◽

Juliana Silva Novais ◽

Beatriz Lima Cosenza de Carvalho ◽

Vitor Francisco Ferreira ◽

Leonardo Alves Miceli ◽

...

Keyword(s):

In Silico ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Mass Spectrometry Analysis ◽

World Health ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Dione Derivative ◽

In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

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The antimicrobial potential of cannabidiol

Communications Biology ◽

10.1038/s42003-020-01530-y ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Mark A. T. Blaskovich ◽

Angela M. Kavanagh ◽

Alysha G. Elliott ◽

Bing Zhang ◽

Soumya Ramu ◽

...

Keyword(s):

Bacterial Infections ◽

Modern Medicine ◽

Gram Negative Bacteria ◽

Gram Negative ◽

New Class ◽

Clostridioides Difficile ◽

Excellent Activity ◽

Induce Resistance ◽

First Time

AbstractAntimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.

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In Vitro and In Vivo Antibacterial Activities of DW-224a, a New Fluoronaphthyridone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01407-05 ◽

2006 ◽

Vol 50 (6) ◽

pp. 2261-2264 ◽

Cited By ~ 36

Author(s):

Hee-Soo Park ◽

Hyun-Joo Kim ◽

Min-Jung Seol ◽

Dong-Rack Choi ◽

Eung-Chil Choi ◽

...

Keyword(s):

Antibacterial Activities ◽

The Other ◽

Vitro Activity ◽

Gram Negative Bacteria ◽

In Vitro Activity ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria

ABSTRACT DW-224a showed the most potent in vitro activity among the quinolone compounds tested against clinical isolates of gram-positive bacteria. Against gram-negative bacteria, DW-224a was slightly less active than the other fluoroquinolones. The in vivo activities of DW-224a against gram-positive bacteria were more potent than those of other quinolones.

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Cefotaxime and amikacin: results of in vitro and in vivo studies against Gram-negative bacteria and Staphylococcus aureus

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/6.suppl_a.55 ◽

1980 ◽

Vol 6 (suppl A) ◽

pp. 55-61 ◽

Cited By ~ 1

Author(s):

J. Klastersky ◽

H. Gaya ◽

S. H. Zinner ◽

C. Bernard ◽

J-C. Ryff ◽

...

Keyword(s):

Staphylococcus Aureus ◽

In Vivo Studies ◽

Gram Negative Bacteria ◽

Gram Negative ◽

And Staphylococcus Aureus

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Structural insights into a novel family of integral membrane siderophore reductases

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101952118 ◽

2021 ◽

Vol 118 (34) ◽

pp. e2101952118

Author(s):

Inokentijs Josts ◽

Katharina Veith ◽

Vincent Normant ◽

Isabelle J. Schalk ◽

Henning Tidow

Keyword(s):

Iron Uptake ◽

Bacterial Species ◽

Gram Negative Bacteria ◽

Inner Membrane ◽

Gram Negative ◽

Inner Membrane Protein ◽

Uptake Studies ◽

Structural Insights

Gram-negative bacteria take up the essential ion Fe3+ as ferric-siderophore complexes through their outer membrane using TonB-dependent transporters. However, the subsequent route through the inner membrane differs across many bacterial species and siderophore chemistries and is not understood in detail. Here, we report the crystal structure of the inner membrane protein FoxB (from Pseudomonas aeruginosa) that is involved in Fe-siderophore uptake. The structure revealed a fold with two tightly bound heme molecules. In combination with in vitro reduction assays and in vivo iron uptake studies, these results establish FoxB as an inner membrane reductase involved in the release of iron from ferrioxamine during Fe-siderophore uptake.

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Synergy and remarkable specificity of antimicrobial peptides in vivo using a systematic knockout approach

eLife ◽

10.7554/elife.44341 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 29

Author(s):

Mark Austin Hanson ◽

Anna Dostálová ◽

Camilla Ceroni ◽

Mickael Poidevin ◽

Shu Kondo ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Fungal Pathogens ◽

Gene Editing ◽

Cationic Peptides ◽

Gram Negative Bacteria ◽

Biological Processes ◽

Gram Negative ◽

Bacteria And Fungi

Antimicrobial peptides (AMPs) are host-encoded antibiotics that combat invading microorganisms. These short, cationic peptides have been implicated in many biological processes, primarily involving innate immunity. In vitro studies have shown AMPs kill bacteria and fungi at physiological concentrations, but little validation has been done in vivo. We utilized CRISPR gene editing to delete most known immune-inducible AMPs of Drosophila, namely: 4 Attacins, 2 Diptericins, Drosocin, Drosomycin, Metchnikowin and Defensin. Using individual and multiple knockouts, including flies lacking these ten AMP genes, we characterize the in vivo function of individual and groups of AMPs against diverse bacterial and fungal pathogens. We found that Drosophila AMPs act primarily against Gram-negative bacteria and fungi, contributing either additively or synergistically. We also describe remarkable specificity wherein certain AMPs contribute the bulk of microbicidal activity against specific pathogens, providing functional demonstrations of highly specific AMP-pathogen interactions in an in vivo setting.

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