Low-toxicity amphiphilic molecules linked by an aromatic nucleus show broad-spectrum antibacterial activity and low drug resistance

2019 ◽  
Vol 55 (30) ◽  
pp. 4307-4310 ◽  
Author(s):  
Wenchao Chu ◽  
Yi Yang ◽  
Shangshang Qin ◽  
Jianfeng Cai ◽  
Mengmeng Bai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antibacterial Activity ◽  
Bactericidal Activity ◽  
Broad Spectrum ◽  
High Selectivity ◽  
Aromatic Nucleus ◽  
Amphiphilic Molecules ◽  
Low Toxicity

Amphiphilic molecules linked by an aromatic nucleus, possessing strong bactericidal activity, high selectivity, less drug resistance, and high in vivo efficacy against MRSA, were developed.

scholarly journals Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

2020 ◽  
Author(s):  
Ozgun Kocabiyik ◽  
Valeria Cagno ◽  
Paulo Jacob Silva ◽  
Yong Zhu ◽  
Laura Sedano ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
New Class ◽  
Influenza Strain ◽  
Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

scholarly journals Antiviral Combination Approach as a Perspective to Combat Enterovirus Infections

PRILOZI ◽  
2015 ◽  
Vol 36 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Angel S. Galabov ◽  
Ivanka Nikolova ◽  
Ralitsa Vassileva-Pencheva ◽  
Adelina Stoyanova
Keyword(s):  
Drug Resistance ◽  
Broad Spectrum ◽  
Main Tool ◽  
Chronic Obstructive ◽  
High Morbidity ◽  
Newborn Mice ◽  
Enteroviral Infection ◽  
Chronic Respiratory Diseases

Abstract Human enteroviruses distributed worldwide are causative agents of a broad spectrum of diseases with extremely high morbidity, including a series of severe illnesses of the central nervous system, heart, endocrine pancreas, skeleton muscles, etc., as well as the common cold contributing to the development of chronic respiratory diseases, including the chronic obstructive pulmonary disease. The above mentioned diseases along with the significantly high morbidity and mortality in children, as well as in the high-risk populations (immunodeficiencies, neonates) definitely formulate the chemotherapy as the main tool for the control of enterovirus infections. At present, clinically effective antivirals for use in the treatment of enteroviral infection do not exist, in spite of the large amount of work carried out in this field. The main reason for this is the development of drug resistance. We studied the process of development of resistance to the strongest inhibitors of enteroviruses, WIN compounds (VP1 protein hydrophobic pocket blockers), especially in the models in vivo, Coxsackievirus B (CV-B) infections in mice. We introduced the tracing of a panel of phenotypic markers (MIC50 value, plaque shape and size, stability at 50℃, pathogenicity in mice) for characterization of the drug-mutants (resistant and dependent) as a very important stage in the study of enterovirus inhibitors. Moreover, as a result of VP1 RNA sequence analysis performed on the model of disoxaril mutants of CVB1, we determined the molecular basis of the drug-resistance. The monotherapy courses were the only approach used till now. For the first time in the research for anti-enterovirus antivirals our team introduced the testing of combination effect of the selective inhibitors of enterovirus replication with different mode of action. This study resulted in the selection of a number of very effective in vitro double combinations with synergistic effect and a broad spectrum of sensitive enteroviruses. The most prospective attainment in our examinations in this field was the development of a novel scheme for the combined application of anti-enteroviral substances in coxsackievirus B1 neuroinfection in newborn mice. It consisted of a consecutive, alternating and non simultaneous administration of the substances in the combination. The triple combination - disoxaril- guanidine. HCl-oxoglaucine (DGO) showed a high effectiveness expressed in the marked reduction of the mortality rate in infected mice as compared both to the placebo group, and to the partner compounds used alone every day, and to the same combination applied simultaneously every day. The studies of the drug sensitivity of viral brain isolates from mice treated with DGO combination showed not only preserved, but even increased sensitivity to the drugs included in the combination. Obviously, the consecutive alternating administration of anti-enteroviral substances hinders the occurrence of drug-resistance in the course of the experimental enteroviral infections in mice.

Assessment of antibacterial property and acute toxicity of phenolic ex-tract of Punica granatum epicarp

2018 ◽  
Vol 7 (5) ◽  
pp. 233-239
Author(s):  
Reguieg Yssaad Athmen ◽  
Hamadi Kheira
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Property ◽  
Intestinal Flora ◽  
Punica Granatum ◽  
Limited Data ◽  
Food Industries ◽  
Phenolic Extract ◽  
Low Toxicity ◽  
The One

The pomegranate (Punica granatum) fruit owing to its beneficial properties for human health is consumed worldwide conventionally. Nevertheless, limited data are available on in vivo antibacterial activity and toxicity of epicarp. Therefore, this research focused on the in vivo study of the acute tox-icity of the phenolic extract of pomegranate bark (Punica granatum) on the one hand, and the evaluation of its antibacterial property on the intestinal flora of another share.In the present study, the LD50 of the calculated meth-anolic extract was included between 500mg/kg, 5000mg / kg and 6000mg / kg). It was observed that the methanolic extract of P. granatum epicarp was of low toxicity. An absence of the pathogenic germs was reported in the ma-jority of the organs of the infected rats, which suggests their elimination by the phenolic extracts of punica granatum, except for the intestine. This work has shown antibacterial activity against Bacillus cereus that can contribute to the fight against infectious diseases and perhaps offer the possibility of using pomegranate bark in pharmaceutical and food industries.

Synthesis and Bioactivities of New Membrane-Active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity

2019 ◽  
Vol 5 (9) ◽  
pp. 1535-1545 ◽  
Author(s):  
Wenchao Chu ◽  
Yi Yang ◽  
Jianfeng Cai ◽  
Hongtao Kong ◽  
Mengmeng Bai ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Broad Spectrum ◽  
High Selectivity

scholarly journals Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
J. Brian McCarthy ◽  
John Mallamo ◽  
Iwao Ojima ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Parent Compound ◽  
Invasive Fungal Infections ◽  
Current Standard ◽  
New Class ◽  
Low Toxicity

ABSTRACT The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, (E)-N′-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N′-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.

scholarly journals Research Progress of Small Molecule Fluorescent Probes for Detecting Hypochlorite

Sensors ◽  
2021 ◽  
Vol 21 (19) ◽  
pp. 6326
Author(s):  
Zhi-Guo Song ◽  
Qing Yuan ◽  
Pengcheng Lv ◽  
Kun Chen
Keyword(s):  
Fluorescent Probes ◽  
High Selectivity ◽  
Hypochlorous Acid ◽  
High Sensitivity ◽  
Chloride Ions ◽  
Research Progress ◽  
Oxygen Species ◽  
Low Toxicity ◽  
Fluorescent Probe Method

Hypochlorous acid (HOCl) generates from the reaction between hydrogen peroxide and chloride ions via myeloperoxidase (MPO)-mediated in vivo. As very important reactive oxygen species (ROS), hypochlorous acid (HOCl)/hypochlorite (OCl−) play a crucial role in a variety of physiological and pathological processes. However, excessive or misplaced production of HOCl/OCl− can cause variety of tissue damage and human diseases. Therefore, rapid, sensitive, and selective detection of OCl− is very important. In recent years, the fluorescent probe method for detecting hypochlorous acid has been developed rapidly due to its simple operation, low toxicity, high sensitivity, and high selectivity. In this review, the progress of recently discovered fluorescent probes for the detection of hypochlorous acid was summarized with the aim to provide useful information for further design of better fluorescent probes.

scholarly journals Potent Broad-Spectrum Antibacterial Activity of Amphiphilic Peptides against Multidrug-Resistant Bacteria

2020 ◽  
Vol 8 (9) ◽  
pp. 1398 ◽  
Author(s):  
Yuan Liu ◽  
Jingru Shi ◽  
Ziwen Tong ◽  
Yuqian Jia ◽  
Kangni Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antibacterial Activity ◽  
Broad Spectrum ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
Resistant Bacteria ◽  
Dependent Manner ◽  
Gram Negative ◽  
E Coli ◽  
Amphiphilic Peptide

The emergence and prevalence of multidrug-resistant (MDR) bacteria particularly Gram-negative bacteria presents a global crisis for human health. Colistin and tigecycline were recognized as the last resort of defenses against MDR Gram-negative pathogens. However, the emergence and prevalence of MCR or Tet(X)-mediated acquired drug resistance drastically impaired their clinical efficacy. It has been suggested that antimicrobial peptides might act a crucial role in combating antibiotic resistant bacteria owing to their multiple modes of action and characteristics that are not prone to developing drug resistance. Herein, we report a safe and stable tryptophan-rich amphiphilic peptide termed WRK-12 with broad-spectrum antibacterial activity against various MDR bacteria, including MRSA, colistin and tigecycline-resistant Escherichia coli. Mechanistical studies showed that WRK-12 killed resistant E. coli through permeabilizing the bacterial membrane, dissipating membrane potential and triggering the production of reactive oxygen species (ROS). Meanwhile, WRK-12 significantly inhibited the formation of an E. coli biofilm in a dose-dependent manner. These findings revealed that amphiphilic peptide WRK-12 is a promising drug candidate in the fight against MDR bacteria.

scholarly journals Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis

2013 ◽  
Vol 58 (2) ◽  
pp. 978-985 ◽  
Author(s):  
Éanna Forde ◽  
Hilary Humphreys ◽  
Catherine M. Greene ◽  
Deirdre Fitzgerald-Hughes ◽  
Marc Devocelle
Keyword(s):  
Cystic Fibrosis ◽  
Host Defense ◽  
Bactericidal Activity ◽  
Neutrophil Elastase ◽  
Activity Levels ◽  
Host Defense Peptides ◽  
Content Type ◽  
Host Defense Peptide ◽  
Low Toxicity

ABSTRACTHost defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities ofPseudomonas aeruginosato parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates ofP. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme atin vivoconcentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

Construction of gambogic acid HPMA Copolymer Coupling drug system and study on anti-tumor activity

2021 ◽  
Vol 18 ◽  
Author(s):  
Xinghua Zhao ◽  
Shi Ding ◽  
Shengnan Li ◽  
Yang Wang ◽  
Mingjun Jiang ◽  
...  
Keyword(s):  
High Selectivity ◽  
High Efficiency ◽  
Gambogic Acid ◽  
Polymer Micelle ◽  
Hpma Copolymer ◽  
Dual Targeting ◽  
New Ideas ◽  
Low Toxicity

Purpose: An active-passive dual-targeting gambogic acid HPMA Copolymer Coupling drug system with high efficiency, low toxicity and high selectivity was constructed. Methods: The gambogic acid HPMA copolymer coupling drug system was constructed and its structure was characterized. The cytotoxicity of gambogic acid HPMA copolymer was detected by MTT assay. The pharmacokinetics of gambogic acid HPMA copolymer was evaluated in mice. Targetability of gambogic acid HPMA copolymer was evaluated by tissue distribution experiment. The in vitro antitumor activity of gambogic acid HPMA copolymer was evaluated by pharmacodynamics experiment in mice. Results : Two copolymers of gambogic acid HPMA were successfully prepared. The copolymers showed reduced cytotoxicity and a certain sustained release effect and targeting property. In vivo pharmacodynamic experiments also showed better anti-tumor effects than GA. Discussion: In this study, gambogic acid was combined with HPMA polymer and the targeting molecule D-galactose/folic acid to form a polymer micelle with high efficiency, low toxicity and high selectivity for active-passive dual targeting. The construction of the drug system provides new ideas for future formulation research and development.

N-doped carbon dots derived from leaves with low toxicity via damaging cytomembrane for broad-spectrum antibacterial activity

2020 ◽  
Vol 24 ◽  
pp. 101222
Author(s):  
Yurong Ma ◽  
Mengling Zhang ◽  
Huibo Wang ◽  
Bo Wang ◽  
Hui Huang ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Broad Spectrum ◽  
Carbon Dots ◽  
Low Toxicity ◽  
Doped Carbon Dots
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