The antimicrobial potential of cannabidiol

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.

Download Full-text

Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

mBio ◽

10.1128/mbio.00674-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 13

Author(s):

Nadine Lemaître ◽

Xiaofei Liang ◽

Javaria Najeeb ◽

Chul-Jin Lee ◽

Marie Titecat ◽

...

Keyword(s):

Bacterial Infections ◽

Biosynthetic Pathway ◽

Lipid A ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Bubonic Plague ◽

Gram Negative ◽

New Class

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.

Download Full-text

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.

Download Full-text

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

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01130-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zaihui Peng ◽

Xiaochun Zhang ◽

Long Yuan ◽

Ting Li ◽

Yajie Chen ◽

...

Keyword(s):

Wound Healing ◽

Bacterial Infections ◽

Antibacterial Properties ◽

Platelet Membrane ◽

Gram Negative Bacteria ◽

Gram Negative ◽

The Impact ◽

Copper Silicate

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

Download Full-text

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.

Download Full-text

Metallothionein 3-Zinc Axis Suppresses Caspase-11 Inflammasome Activation and Impairs Antibacterial Immunity

Frontiers in Immunology ◽

10.3389/fimmu.2021.755961 ◽

2021 ◽

Vol 12 ◽

Author(s):

Debabrata Chowdhury ◽

Jason C. Gardner ◽

Abhijit Satpati ◽

Suba Nookala ◽

Santhosh Mukundan ◽

...

Keyword(s):

Bacterial Infections ◽

Negative Regulation ◽

Effector Function ◽

Inflammasome Activation ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Human Macrophages ◽

Inflammatory Damage ◽

Human Caspase

Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE-4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. In vivo, MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram-negative bacteria.

Download Full-text

A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

10.26434/chemrxiv.14208287.v1 ◽

2021 ◽

Author(s):

Xingguang Cai ◽

Sacha Javor ◽

Bee-Ha Gan ◽

Thilo Köhler ◽

Jean-Louis Reymond

Keyword(s):

Bacterial Infections ◽

Chronic Wounds ◽

Ph Dependence ◽

Polymyxin B ◽

Antibiotic Activity ◽

Gram Negative Bacteria ◽

Gram Negative ◽

New Class ◽

Peptide Dendrimers ◽

Lysine Residues

In our efforts to develop peptide dendrimers as a new class of antimicrobial peptides (AMPs) against Gram-negative bacteria, we investigated their activity at acidic and basic pH, which correspond to the conditions of the site of bacterial infections on skin or biofilms and chronic wounds respectively. Removing the eight low pKa amino termini of our reference dendrimer G3KL by substituting the N-terminal lysine residues with aminohexanoic acid provided dendrimer XC1 with a broader pH-activity range. Furthermore, raising the pH to 8.0 revealed strong activities against Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA) against which the dendrimers are inactive at pH 7.4, an effect which we also observed with polymyxin B and tentatively assign to stronger binding to the bacteria at higher pH as observed with a fluorescence labeled dendrimer analog.

Download Full-text

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.

Download Full-text

A Study with Peptide Dendrimers Reveals an Extreme pH Dependence of Antibiotic Activity Above pH 7.4

10.26434/chemrxiv.14208287.v2 ◽

2021 ◽

Author(s):

Xingguang Cai ◽

Sacha Javor ◽

Bee-Ha Gan ◽

Thilo Köhler ◽

Jean-Louis Reymond

Keyword(s):

Bacterial Infections ◽

Chronic Wounds ◽

Ph Dependence ◽

Polymyxin B ◽

Antibiotic Activity ◽

Gram Negative Bacteria ◽

Gram Negative ◽

New Class ◽

Peptide Dendrimers ◽

Lysine Residues

Download Full-text

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.

Download Full-text

Ultrastructural studies of Chlamydia psittaci 6BC variant strains. I. Ultrastructure of the surface layers of egg-passaged 6BC strain

Canadian Journal of Microbiology ◽

10.1139/m73-142 ◽

1973 ◽

Vol 19 (8) ◽

pp. 887-894

Author(s):

Linda Poffenroth ◽

J. W. Costerton ◽

Nonna Kordová ◽

John C. Wilt

Keyword(s):

Chick Embryo ◽

Microscopic Examination ◽

Electron Microscopic Examination ◽

Chlamydia Psittaci ◽

Gram Negative Bacteria ◽

Surface Layers ◽

Electron Microscopic ◽

Gram Negative ◽

Ultrastructural Studies ◽

First Time

Electron microscopic examination of a semipurified Chlamydia psittaci 6BC strain attenuated in chick embryo yolk sac revealed for the first time two morphologically distinct small elementary bodies which differ both in the ultrastructure of their surface layers and in their buoyant densities in sucrose gradients. Also, the morphology of the surface layers of the larger reticulate forms in cell-free systems is described for the first time. Many points of difference between the surface envelopes and internal structure of chlamydial particles and those of Gram-negative bacteria are discussed.

Download Full-text