Bioguided Isolation of Antibiofilm and Antibacterial Pregnane Glycosides from Caralluma quadrangula: Disarming Multidrug-Resistant Pathogens

Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii (MDRAB) present a serious challenge because of their capability to cause biofilm resistance to commonly used antibiotics producing chronic infections and hindering the process of wound healing. In the current study, we investigated the antibacterial activity of Caralluma quadrangula extracts (MeOH, and its fractions CH2Cl2 and n-butanol) against multidrug-resistant MRSA USA300 and A. baumannii AB5057. In vitro, the MeOH extract and both fractions of C. quadrangula significantly inhibited biofilm formation and disrupted previously established biofilm by MRSA and MDRAB at all the tested concentrations (0.625, 0.313, and 0.156 mg/mL). In vivo, C. quadrangula extracts successfully decreased bacterial loads in MRSA-infected skin lesions in mice. Four pregnane glycosides and one flavone glycoside were isolated from the bioactive n-butanol fraction. The isolated compounds (Rus A–E) were tested for their biofilm inhibition and biofilm detachment activities. The results revealed that Rus C was the most active compound (IC50 = 0.139 mmole), while Rus E was the least active (IC50 = 0.818 mmole). These results support the potential use of C. quadrangula extracts or their isolated compounds for hindering the biofilm attachment and the virulence of MRSA and MDRAB and their application as a topical antimicrobial preparation for MRSA skin infections.

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Amphiphilic Triazine Polymer Derivatives as Antibacterial And Anti-atopic Agents in Mice Model

Scientific Reports ◽

10.1038/s41598-019-51561-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Pethaiah Gunasekaran ◽

meiqi Fan ◽

Eun Young Kim ◽

Jun Ho Shin ◽

Ji Eun Lee ◽

...

Keyword(s):

Bacterial Resistance ◽

Bacterial Colonization ◽

Skin Lesions ◽

Multidrug Resistant ◽

Significant Inhibition ◽

Amide Bond ◽

Mice Model ◽

The Impact

Abstract Considering the emergence of bacterial resistance and low proteolytic stability of antimicrobial peptides (AMPs), herein we developed a series of ultra-short triazine based amphipathic polymers (TZP) that are connected with ethylene diamine linkers instead of protease sensitive amide bond. The most potent oligomers, TZP3 and TZP5 not only displayed potent antibacterial action on various drug-resistant pathogens but also exhibited a strong synergic antibacterial activity in combination with chloramphenicol against multidrug-resistant Pseudomonas aeruginosa (MDRPA). Since most of atopic dermatitis (AD) infections are caused by bacterial colonization, we evaluated the potency of TZP3 and TZP5 on AD in vitro and in vivo. In vitro AD analysis of these two polymers showed significant inhibition against the release of β-hexosaminidase and tumor necrosis factor (TNF-α) from RBL-2H3 cells. In AD-like skin lesions in BALB/c mice model, these two polymers displayed significant potency in suppressing dermal and epidermal thickness, mast cell infiltration and pro-inflammatory cytokines expression. Moreover, these polymers exhibited remarkable efficacy over the allergies caused by the imbalance of Th1/Th2 by regulating total IgE and IgG2a. Finally, the impact of treatment effects of these polymers was examined through analyzing the weights and sizes of spleen and lymph node of AD-induced mice.

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In silicoidentification of novel peptides with antibacterial activity against multidrug resistantStaphylococcus aureus

10.1101/577221 ◽

2019 ◽

Author(s):

Linda B Oyama ◽

Hamza Olleik ◽

Ana Carolina Nery Teixeira ◽

Matheus M Guidini ◽

James A Pickup ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Peptides ◽

In Silico ◽

Multidrug Resistant ◽

Biofilm Inhibition ◽

Methicillin Resistant ◽

Drug Candidates ◽

Wide Range

AbstractHerein we report the identification and characterisation of two linear antimicrobial peptides (AMPs), HG2 and HG4, with activity against a wide range of multidrug resistant (MDR) bacteria, especially methicillin resistantStaphylococcus aureus(MRSA) strains, a highly problematic group of Gram-positive bacteria in the hospital and community environment. To identify the novel AMPs presented here, we employed the classifier model design, a feature extraction method using molecular descriptors for amino acids for the analysis, visualization, and interpretation of AMP activities from a rumen metagenomic dataset. This allowed for thein silicodiscrimination of active and inactive peptides in order to define a small number of promising novel lead AMP test candidates for chemical synthesis and experimental evaluation.In vitrodata suggest that the chosen AMPs are fast acting, show strong biofilm inhibition and dispersal activity and are efficacious in anin vivomodel of MRSA USA300 infection, whilst showing little toxicity to human erythrocytes and human primary cell linesex vivo. Observations from biophysical AMP-lipid-interactions and electron microscopy suggest that the newly identified peptides interact with the cell membrane and may be involved in the inhibition of other cellular processes. Amphiphilic conformations associated with membrane disruption are also observed in 3D molecular modelling of the peptides. HG2 and HG4 both preferentially bind to MRSA total lipids rather than with human cell lipids indicating that HG4 may form superior templates for safer therapeutic candidates for MDR bacterial infections.Author SummaryWe are losing our ability to treat multidrug resistant (MDR) bacteria, otherwise known as superbugs. This poses a serious global threat to human health as bacteria are increasingly acquiring resistance to antibiotics. There is therefore urgent need to intensify our efforts to develop new safer alternative drug candidates. We emphasise the usefulness of complementing wet-lab andin silicotechniques for the rapid identification of new drug candidates from environmental samples, especially antimicrobial peptides (AMPs). HG2 and HG4, the AMPs identified in our study show promise as effective therapies for the treatment of methicillin resistantStaphylococcus aureusinfections bothin vitroandin vivowhilst having little cytotoxicity against human primary cells, a step forward in the fight against MDR infections.

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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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Traditional Herbal Medicines, Newer Herbs and Other Novel Approaches Integrated in Herbal Medicine for Atopic Dermatitis-A Narrative Review

Current Drug Therapy ◽

10.2174/1574885514666191018165209 ◽

2020 ◽

Vol 15 (3) ◽

pp. 194-208

Author(s):

Pravin Kumar ◽

Dinesh Kumar Sharma ◽

Mahendra Singh Ashawat

Keyword(s):

Atopic Dermatitis ◽

Herbal Medicines ◽

Developed Countries ◽

Skin Lesions ◽

Scientific Data ◽

Herbal Drugs ◽

Biological Drugs ◽

Alternative Treatment Option

Atopic Dermatitis (AD) is a prolonged reverting skin ailment with characteristically distributed skin lesions. In the previous decades, researchers had shown a marked interest in AD due to its increased prevalence in developed countries. Although different strategies including biological and immune modulators are available for the treatment of AD, each has certain limitations. The researchers had shown considerable interest in the management of AD with herbal medicines. The establishment of herbal drugs for AD might eliminate local as well as systemic adverse effects associated with long term use of corticosteroids and also higher cost of therapy with biological drugs. The present review discusses the traditional East Asian herbal medicines and scientific data related to newer herbal extracts or compositions for the treatment of AD. In vivo animal models and in vitro cell cultures, investigated with herbal medicines to establish a possible role in AD treatment, have also been discussed in the paper. The paper also highlights the role of certain new approaches, i.e. pharmacopuncture, a combination of allopathic and herbal medicines; and novel carriers (liposomes, cubosomes) for herbal drugs on atopic skin. In conclusion, herbal medicines can be a better and safe, complementary and alternative treatment option for AD.

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In Vitro Newly Isolated Environmental Phage Activity against Biofilms Preformed by Pseudomonas aeruginosa from Patients with Cystic Fibrosis

Microorganisms ◽

10.3390/microorganisms9030478 ◽

2021 ◽

Vol 9 (3) ◽

pp. 478

Author(s):

Ersilia Vita Fiscarelli ◽

Martina Rossitto ◽

Paola Rosati ◽

Nour Essa ◽

Valentina Crocetta ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Multidrug Resistant ◽

In Vitro Test ◽

Chronic Infections ◽

Hospital Environments ◽

Vitro Test ◽

General Reliability ◽

Phage Activity

As disease worsens in patients with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) colonizes the lungs, causing pulmonary failure and mortality. Progressively, PA forms typical biofilms, and antibiotic treatments determine multidrug-resistant (MDR) PA strains. To advance new therapies against MDR PA, research has reappraised bacteriophages (phages), viruses naturally infecting bacteria. Because few in vitro studies have tested phages on CF PA biofilms, general reliability remains unclear. This study aimed to test in vitro newly isolated environmental phage activity against PA isolates from patients with CF at Bambino Gesù Children’s Hospital (OBG), Rome, Italy. After testing in vitro phage activities, we combined phages with amikacin, meropenem, and tobramycin against CF PA pre-formed biofilms. We also investigated new emerging morphotypes and bacterial regrowth. We obtained 22 newly isolated phages from various environments, including OBG. In about 94% of 32 CF PA isolates tested, these phages showed in vitro PA lysis. Despite poor efficacy against chronic CF PA, five selected-lytic-phages (Φ4_ZP1, Φ9_ZP2, Φ14_OBG, Φ17_OBG, and Φ19_OBG) showed wide host activity. The Φ4_ZP1-meropenem and Φ14_OBG-tobramycin combinations significantly reduced CF PA biofilms (p < 0.001). To advance potential combined phage-antibiotic therapy, we envisage further in vitro test combinations with newly isolated phages, including those from hospital environments, against CF PA biofilms from early and chronic infections.

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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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Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients

Pharmaceuticals ◽

10.3390/ph14040336 ◽

2021 ◽

Vol 14 (4) ◽

pp. 336

Author(s):

Annalisa Noce ◽

Maria Albanese ◽

Giulia Marrone ◽

Manuela Di Lauro ◽

Anna Pietroboni Zaitseva ◽

...

Keyword(s):

Adjuvant Treatment ◽

Pulmonary Involvement ◽

In Vivo Studies ◽

Pharmacological Treatments ◽

Beneficial Effects ◽

Coronavirus Infection ◽

Ultramicronized Palmitoylethanolamide ◽

Potential Use

The Coronavirus Disease-19 (COVID-19) pandemic has caused more than 100,000,000 cases of coronavirus infection in the world in just a year, of which there were 2 million deaths. Its clinical picture is characterized by pulmonary involvement that culminates, in the most severe cases, in acute respiratory distress syndrome (ARDS). However, COVID-19 affects other organs and systems, including cardiovascular, urinary, gastrointestinal, and nervous systems. Currently, unique-drug therapy is not supported by international guidelines. In this context, it is important to resort to adjuvant therapies in combination with traditional pharmacological treatments. Among natural bioactive compounds, palmitoylethanolamide (PEA) seems to have potentially beneficial effects. In fact, the Food and Drug Administration (FDA) authorized an ongoing clinical trial with ultramicronized (um)-PEA as an add-on therapy in the treatment of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. In support of this hypothesis, in vitro and in vivo studies have highlighted the immunomodulatory, anti-inflammatory, neuroprotective and pain-relieving effects of PEA, especially in its um form. The purpose of this review is to highlight the potential use of um-PEA as an adjuvant treatment in SARS-CoV-2 infection.

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Pseudomonas aeruginosa PAO 1 In Vitro Time–Kill Kinetics Using Single Phages and Phage Formulations—Modulating Death, Adaptation, and Resistance

Antibiotics ◽

10.3390/antibiotics10070877 ◽

2021 ◽

Vol 10 (7) ◽

pp. 877

Author(s):

Ana Mafalda Pinto ◽

Alberta Faustino ◽

Lorenzo M. Pastrana ◽

Manuel Bañobre-López ◽

Sanna Sillankorva

Keyword(s):

Pseudomonas Aeruginosa ◽

Phage Therapy ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Chronic Infections ◽

Swarming Motility ◽

Resistance Development ◽

Healthcare Settings ◽

Time Kill

Pseudomonas aeruginosa is responsible for nosocomial and chronic infections in healthcare settings. The major challenge in treating P. aeruginosa-related diseases is its remarkable capacity for antibiotic resistance development. Bacteriophage (phage) therapy is regarded as a possible alternative that has, for years, attracted attention for fighting multidrug-resistant infections. In this work, we characterized five phages showing different lytic spectrums towards clinical isolates. Two of these phages were isolated from the Russian Microgen Sextaphage formulation and belong to the Phikmvviruses, while three Pbunaviruses were isolated from sewage. Different phage formulations for the treatment of P. aeruginosa PAO1 resulted in diversified time–kill outcomes. The best result was obtained with a formulation with all phages, prompting a lower frequency of resistant variants and considerable alterations in cell motility, resulting in a loss of 73.7% in swimming motility and a 79% change in swarming motility. These alterations diminished the virulence of the phage-resisting phenotypes but promoted their growth since most became insensitive to a single or even all phages. However, not all combinations drove to enhanced cell killings due to the competition and loss of receptors. This study highlights that more caution is needed when developing cocktail formulations to maximize phage therapy efficacy. Selecting phages for formulations should consider the emergence of phage-resistant bacteria and whether the formulations are intended for short-term or extended antibacterial application.

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Therapeutic effects of EGF-modified curcumin/chitosan nano-spray on wound healing

Regenerative Biomaterials ◽

10.1093/rb/rbab009 ◽

2021 ◽

Vol 8 (2) ◽

Author(s):

Yue Li ◽

QingQing Leng ◽

XianLun Pang ◽

Huan Shi ◽

YanLin Liu ◽

...

Keyword(s):

Drug Delivery ◽

Wound Healing ◽

Chitosan Nanoparticles ◽

Skin Lesions ◽

In Vitro Assays ◽

Therapeutic Effects ◽

Skin Defects ◽

Post Operation

Abstract Dermal injury, including trauma, surgical incisions, and burns, remain the most prevalent socio-economical health care issue in the clinic. Nanomedicine represents a reliable administration strategy that can promote the healing of skin lesions, but the lack of effective drug delivery methods can limit its effectiveness. In this study, we developed a novel nano-drug delivery system to treat skin defects through spraying. We prepared curcumin-loaded chitosan nanoparticles modified with epidermal growth factor (EGF) to develop an aqueous EGF-modified spray (EGF@CCN) for the treatment of dermal wounds. In vitro assays showed that the EGF@CCN displayed low cytotoxicity, and that curcumin was continuously and slowly released from the EGF@CCN. In vivo efficacy on wound healing was then evaluated using full-thickness dermal defect models in Wistar rats, showing that the EGF@CCN had significant advantages in promoting wound healing. On day 12 post-operation, skin defects in the rats of the EGF@CCN group were almost completely restored. These effects were related to the activity of curcumin and EGF on skin healing, and the high compatibility of the nano formulation. We therefore conclude that the prepared nano-scaled EGF@CCN spray represents a promising strategy for the treatment of dermal wounds.

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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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