Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA) (original) (raw)
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Clinical Microbiology: Open Access, 2017
Antimicrobial peptides are widely preferred drugs for infectious disease treatment. Inspired from natural antimicrobial peptides, short peptides showing good antibacterial activity are designed in this study. The peptides consisted of repeating hydrophobic and positively charged amino acids, positioned on one side of the alpha helix. Arginine in peptides resulted in better activity compared to lysine. Having positively charged amino acids at both ends, created better activity for Escherichia coli compared to Staphylococcus aureus, and only at one end, created comparable activities for both organisms. Positioning of arginines on one side in zigzag form prominently increased the activity compared to positioning on linear axis. Elongating hydrophobic tail resulted in self-binding and eliminated the antibacterial activity. Molecular dynamic simulations suggested that a single molecule is capable of creating hydrophilic channel in membrane. Electron microscopic examination of staphylococci treated with these peptides revealed that the bacteria split into halves. Docking studies revealed that the peptides strongly bind to the major peptidoglycan synthesizing membrane protein, glycosyltransferase. The unique composition and design of these peptides revealed a promising antibacterial activity that may further lead to the development of new antimicrobial compounds effective to multi-drug resistant organisms.
Antimicrobial peptides: natural templates for synthetic membrane-active compounds
The innate immunity of multicellular organisms relies in large part on the action of antimicrobial peptides (AMPs) to resist microbial invasion. Crafted by evolution into an extremely diversified array of sequences and folds, AMPs do share a common amphiphilic 3-Darrangement.This feature is directly linked with a common mechanism of action that predominantly (although not exclusively) develops upon interaction of peptides with cell membranes of target cells. This minireview reports on current understanding of the modes of interaction of AMPs with biological and model membranes, especially focusing on recent insights into the folding and oligomerization requirements of peptides to bind and insert into lipid membranes and exert their antibiotic effects. Given the potential of AMPs to be developed into a new class of anti-infective agents, emphasis is placed on how the information on peptidemembrane interactions could direct the design and selection of improved biomimetic synthetic peptides with antibiotic properties
Scientific reports, 2016
Methicillin-resistant Staphylococcus aureus (MRSA) infections present a serious challenge because of the emergence of resistance to numerous conventional antibiotics. Due to their unique mode of action, antimicrobial peptides are novel alternatives to traditional antibiotics for tackling the issue of bacterial multidrug resistance. Herein, we investigated the antibacterial activity of two short novel peptides (WR12, a 12 residue peptide composed exclusively of arginine and tryptophan, and D-IK8, an eight residue β-sheet peptide) against multidrug resistant staphylococci. In vitro, both peptides exhibited good antibacterial activity against MRSA, vancomycin-resistant S. aureus, linezolid-resistant S. aureus, and methicillin-resistant S. epidermidis. WR12 and D-IK8 were able to eradicate persisters, MRSA in stationary growth phase, and showed significant clearance of intracellular MRSA in comparison to both vancomycin and linezolid. In vivo, topical WR12 and D-IK8 significantly reduce...
Current Challenges in the Discovery of Novel Antibacterials from Microbial Natural Products
PRI, 2012
Methicillin-resistant Staphylococcus aureus (MRSA) plays a significant role in the pandemic of multidrug resistant bacterial infections and is a major cause of hospital-acquired pneumonia. MRSA pneumonia carries a high morbidity and mortality rate especially in elderly diabetics with chronic kidney disease. S. aureus is highly virulent and successful respiratory pathogen. Vancomycin and linezolid are the only two antimicrobial agents FDA-approved to treat MRSA pneumonia. Standard vancomycin dosing is associated with high clinical failure rates and higher dosages are associated with increased nephrotoxicity. Pharmacokinetic and pharmacodynamic limitations are major contributors to poor outcomes with vancomycin. New agents are needed to improve treatment outcomes with MRSA pneumonia. Recently released antimicrobials with in vitro activity are not FDA-approved for treating MRSA pneumonia. Other novel agents are being investigated though none are in late-stage development. Pharmaceutical industry perception of low returns on investment, a Sisyphean regulatory environment, and obstacles to patentability have contributed to declining interest in both the development of novel antibiotics and the improvement of existing generic formulations. Despite decades of investigation into liposomal encapsulation as a drug delivery system that would increase efficacy and decrease toxicity, only liposomal amphotericin B and doxorubicin are commercially available. In this article, the pharmacokinetics and biodistribution of a novel PEGylated liposomal vancomycin formulation along with passive targeting and the enhanced permeability and retention effect of liposomal drug delivery; the pathogenesis of MRSA pneumonia; and recent patents of novel anti-MRSA agents, including inhalational liposomal vancomycin, are reviewed.
Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides
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Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing...
International journal of health sciences
Antimicrobial peptides (AMPs) are a family of tiny peptides found throughout nature that play a vital role in various organisms' innate immune systems. Antimicrobial peptides and proteins (AMPs) are a varied family of naturally occurring chemicals produced by all multicellular organisms as a first line of defense. The rising prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) diseases is the most evident cause for concern. Traditional antimicrobial drugs work by targeting certain metabolic pathways or microbiological structures to kill or hinder bacterial growth. The development of new lead structures to combat multidrug-resistant bacteria is critical, and cationic antimicrobial peptides (AMPs) have the ability to do so. Based on the SPOT synthesis, we present an outline of a strategy for screening peptides for antimicrobial activity. Multidrug-resistant bacteria have grown fast in recent decades, leading to a rise in nosocomial infections and in-hospita...
Bioorganic chemistry, 2018
Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norflo...
Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies
SLAS Discovery, 2019
Over the past century, a multitude of derivatives of structural scaffolds with established antimicrobial potential have been prepared and tested, and a variety of new scaffolds have emerged. The effectiveness of antibiotics, however, is in sharp decline because of the emergence of drug-resistant microorganisms. The prevalence of drug resistance, both in clinical and community settings, is a consequence of bacterial ingenuity in altering pathways and/or cell morphology, making it a persistent threat to human health. The fundamental ability of pathogens to survive in a multitude of habitats can be triggered by recognition of chemical signals that warn organisms of exposure to a potentially harmful environment. Host immune defenses, including reactive oxygen intermediates and antibacterial substances, are among the multitude of chemical signals that can subsequently trigger expression of phenotypes better adapted for survival in that hostile environment. Thus, resistance development ap...
The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs
Molecules (Basel, Switzerland), 2018
Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) they act synergically with conventional antibiotics; (4) they neutralize endotoxins and are active in animal models. However, it is considered that many natural peptides are not suitable for drug development due to stability and biodisponibility problems, or high production costs. This review describes the efforts to overcome these problems and develop new antimicrobial drugs from these peptides or inspired by them. The discovery process of natural AMPs is discussed, as well as the development of synthetic analogs with improved pharmacological properties. The production of these compounds at acceptable costs, using different chemical and biotechnological methods, is also commente...
PloS one, 2018
The emergence of pathogenic multidrug-resistant bacteria demands new approaches in finding effective antibacterial agents. Synthetic flavonoids could be a reliable solution due to their important antimicrobial activity. We report here the potent in vitro antibacterial activity of ClCl-flav-a novel synthetic tricyclic flavonoid. The antimicrobial effects were tested using the minimum inhibitory concentration (MIC), time kill and biofilm formation assays. Fluorescence microscopy and scanning electron microscopy were employed to study the mechanism of action. MTT test was used to assess the cytotoxicity of ClCl-flav. Our results showed that Gram positive bacteria were more sensitive (MIC = 0.24 μg/mL) to ClCl-flav compared to the Gram negative ones (MIC = 3.9 μg/mL). We found that our compound showed significantly enhanced antibacterial activities, 32 to 72-fold more active than other synthetic flavonoids. ClCl-flav showed bactericidal activity at concentrations ranging from 0.48 to 15...