scholarly journals Imcroporin, a New Cationic Antimicrobial Peptide from the Venom of the Scorpion Isometrus maculates

2009 ◽  
Vol 53 (8) ◽  
pp. 3472-3477 ◽  
Author(s):  
Zhenhuan Zhao ◽  
Yibao Ma ◽  
Chao Dai ◽  
Ruiming Zhao ◽  
SongRyong Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Lead Compound ◽  
Cationic Antimicrobial Peptide ◽  
Antibiotic Resistant ◽  
Multidrug Resistant Pathogens ◽  
Conventional Antibiotics

ABSTRACT The pace of resistance against antibiotics almost exceeds that of the development of new drugs. As many bacteria have become resistant to conventional antibiotics, new drugs or drug resources are badly needed to combat antibiotic-resistant pathogens, like methicillin-resistant Staphylococcus aureus (MRSA). Antimicrobial peptides, rich sources existing in nature, are able to effectively kill multidrug-resistant pathogens. Here, imcroporin, a new antimicrobial peptide, was screened and isolated from the cDNA library of the venomous gland of Isometrus maculates. The MIC of imcroporin against MRSA was 50 μg/ml, 8-fold lower than that of cefotaxime and 40-fold lower than that of penicillin. Imcroporin killed bacteria rapidly in vitro, inhibited bacterial growth, and cured infected mice. These results revealed that imcroporin could be considered a potential anti-infective drug or lead compound, especially for treating antibiotic-resistant pathogens.

scholarly journals Antimicrobial Peptide Novicidin Synergizes with Rifampin, Ceftriaxone, and Ceftazidime against Antibiotic-Resistant EnterobacteriaceaeIn Vitro

2015 ◽  
Vol 59 (10) ◽  
pp. 6233-6240 ◽  
Author(s):  
Odel Soren ◽  
Karoline Sidelmann Brinch ◽  
Dipesh Patel ◽  
Yingjun Liu ◽  
Alexander Liu ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Bacterial Infections ◽  
New Drugs ◽  
Gram Negative Bacteria ◽  
Cationic Antimicrobial Peptide ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Resistant Strains ◽  
Multiple Strains

ABSTRACTThe spread of antibiotic resistance among Gram-negative bacteria is a serious clinical threat, and infections with these organisms are a leading cause of mortality worldwide. Traditional novel drug development inevitably leads to the emergence of new resistant strains, rendering the new drugs ineffective. Therefore, reviving the therapeutic potentials of existing antibiotics represents an attractive novel strategy. Novicidin, a novel cationic antimicrobial peptide, is effective against Gram-negative bacteria. Here, we investigated novicidin as a possible antibiotic enhancer. The actions of novicidin in combination with rifampin, ceftriaxone, or ceftazidime were investigated against 94 antibiotic-resistant clinical Gram-negative isolates and 7 strains expressing New Delhi metallo-β-lactamase-1. Using the checkerboard method, novicidin combined with rifampin showed synergy with >70% of the strains, reducing the MICs significantly. The combination of novicidin with ceftriaxone or ceftazidime was synergistic against 89.7% of the ceftriaxone-resistant strains and 94.1% of the ceftazidime-resistant strains. Synergistic interactions were confirmed using time-kill studies with multiple strains. Furthermore, novicidin increased the postantibiotic effect when combined with rifampin or ceftriaxone. Membrane depolarization assays revealed that novicidin alters the cytoplasmic membrane potential of Gram-negative bacteria.In vitrotoxicology tests showed novicidin to have low hemolytic activity and no detrimental effect on cell cultures. We demonstrated that novicidin strongly rejuvenates the therapeutic potencies of ceftriaxone or ceftazidime against resistant Gram-negative bacteriain vitro. In addition, novicidin boosted the activity of rifampin. This strategy can have major clinical implications in our fight against antibiotic-resistant bacterial infections.

scholarly journals The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Wooseong Kim ◽  
Guijin Zou ◽  
Wen Pan ◽  
Nico Fricke ◽  
Hammad A. Faizi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Lipid Bilayers ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Lead Compound ◽  
Neutral Form ◽  
Cationic Form ◽  
Antibiotic Resistant ◽  
Content Type

ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.

scholarly journals Design, Overproduction and Purification of the Chimeric Phage Lysin MLTphg Fighting against Staphylococcus aureus

Processes ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 1587
Author(s):  
Feng Wang ◽  
Xiaohang Liu ◽  
Zhengyu Deng ◽  
Yao Zhang ◽  
Xinyu Ji ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Conventional Antibiotics ◽  
Phage Lysin ◽  
Shed Light

With the increasing spread of multidrug-resistant bacterial pathogens, it is of great importance to develop alternatives to conventional antibiotics. Here, we report the generation of a chimeric phage lysin, MLTphg, which was assembled by joining the lysins derived from Meiothermus bacteriophage MMP7 and Thermus bacteriophage TSP4 with a flexible linker via chimeolysin engineering. As a potential antimicrobial agent, MLTphg can be obtained by overproduction in Escherichia coli BL21(DE3) cells and the following Ni-affinity chromatography. Finally, we recovered about 40 ± 1.9 mg of MLTphg from 1 L of the host E. coli BL21(DE3) culture. The purified MLTphg showed peak activity against Staphylococcus aureus ATCC6538 between 35 and 40 °C, and maintained approximately 44.5 ± 2.1% activity at room temperature (25 °C). Moreover, as a produced chimera, it exhibited considerably improved bactericidal activity against Staphylococcus aureus (2.9 ± 0.1 log10 reduction was observed upon 40 nM MLTphg treatment at 37 °C for 30 min) and also a group of antibiotic-resistant bacteria compared to its parental lysins, TSPphg and MMPphg. In the current age of growing antibiotic resistance, our results provide an engineering basis for developing phage lysins as novel antimicrobial agents and shed light on bacteriophage-based strategies to tackle bacterial infections.

scholarly journals Design and Preclinical Development of a Phage Product for the Treatment of Antibiotic-Resistant Staphylococcus aureus Infections

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 88 ◽  
Author(s):  
Susan Lehman ◽  
Gillian Mearns ◽  
Deborah Rankin ◽  
Robert Cole ◽  
Frenk Smrekar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Phase 1 ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Preclinical Development ◽  
Antibiotic Resistant ◽  
Fixed Composition ◽  
Spontaneous Frequency

Bacteriophages, viruses that only kill specific bacteria, are receiving substantial attention as nontraditional antibacterial agents that may help alleviate the growing antibiotic resistance problem in medicine. We describe the design and preclinical development of AB-SA01, a fixed-composition bacteriophage product intended to treat Staphylococcus aureus infections. AB-SA01 contains three naturally occurring, obligately lytic myoviruses related to Staphylococcus phage K. AB-SA01 component phages have been sequenced and contain no identifiable bacterial virulence or antibiotic resistance genes. In vitro, AB-SA01 killed 94.5% of 401 clinical Staphylococcus aureus isolates, including methicillin-resistant and vancomycin-intermediate ones for a total of 95% of the 205 known multidrug-resistant isolates. The spontaneous frequency of resistance to AB-SA01 was ≤3 × 10−9, and resistance emerging to one component phage could be complemented by the activity of another component phage. In both neutropenic and immunocompetent mouse models of acute pneumonia, AB-SA01 reduced lung S. aureus populations equivalently to vancomycin. Overall, the inherent characteristics of AB-SA01 component phages meet regulatory and generally accepted criteria for human use, and the preclinical data presented here have supported production under good manufacturing practices and phase 1 clinical studies with AB-SA01.

Chlorhexidine Resistance in Antibiotic-Resistant Bacteria Isolated From the Surfaces of Dispensers of Soap Containing Chlorhexidine

2002 ◽  
Vol 23 (11) ◽  
pp. 692-695 ◽  
Author(s):  
Steven E. Brooks ◽  
Mary A. Walczak ◽  
Rizwanullah Hameed ◽  
Patrick Coonan
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Contamination ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibiotic Resistant Bacteria ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Methicillin Resistant

AbstractBacterial contamination with pan-resistant Acinetobacter and Klebsiella, multidrug-resistant Pseudomonas, and methicillin-resistant Staphylococcus aureus (MRSA) was noted on the surfaces of dispensers of hand soap with 2% chlorhexidine. Gram-negative isolates could multiply in the presence of 1% chlorhexidine. In contrast, MRSA was inhibited in vitro by chlorhexidine at concentrations as low as 0.0019%.

scholarly journals Random Mutagenesis of theAspergillus oryzaeGenome Results in Fungal Antibacterial Activity

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Cory A. Leonard ◽  
Stacy D. Brown ◽  
J. Russell Hayman
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Random Mutagenesis ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Resistant Bacteria ◽  
Klebsiella Pneumonia ◽  
Antibacterial Compounds ◽  
Severe Infections

Multidrug-resistant bacteria cause severe infections in hospitals and communities. Development of new drugs to combat resistant microorganisms is needed. Natural products of microbial origin are the source of most currently available antibiotics. We hypothesized that random mutagenesis ofAspergillus oryzaewould result in secretion of antibacterial compounds. To address this hypothesis, we developed a screen to identify individualA. oryzaemutants that inhibit the growth of Methicillin-resistantStaphylococcus aureus(MRSA)in vitro. To randomly generateA. oryzaemutant strains, spores were treated with ethyl methanesulfonate (EMS). Over 3000 EMS-treatedA. oryzaecultures were tested in the screen, and one isolate, CAL220, exhibited altered morphology and antibacterial activity. Culture supernatant from this isolate showed antibacterial activity against Methicillin-sensitiveStaphylococcus aureus, MRSA, andPseudomonas aeruginosa, but notKlebsiella pneumoniaorProteus vulgaris. The results of this study support our hypothesis and suggest that the screen used is sufficient and appropriate to detect secreted antibacterial fungal compounds resulting from mutagenesis ofA. oryzae. Because the genome ofA. oryzaehas been sequenced and systems are available for genetic transformation of this organism, targeted as well as random mutations may be introduced to facilitate the discovery of novel antibacterial compounds using this system.

scholarly journals In Vitro Evaluation of Antimicrobial Activity and Cytotoxicity of Different Nanobiotics Targeting Multidrug Resistant and Biofilm Forming Staphylococci

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Mennatallah A. Mohamed ◽  
Maha Nasr ◽  
Walid F. Elkhatib ◽  
Wafaa N. Eltayeb
Keyword(s):  
Antimicrobial Activity ◽  
Rat Hepatocytes ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Antibiotic Resistant ◽  
Diphenyltetrazolium Bromide ◽  
New Antibiotics ◽  
Conventional Antibiotics

Antibiotic-resistant and biofilm-forming bacteria have surprisingly increased over recent years. On the contrary, the rate of development of new antibiotics to treat these emerging superbugs is very slow. Therefore, the aim of this study was to prepare novel nanobiotic formulations to improve the antimicrobial activity of three antibiotics (linezolid, doxycycline, and clindamycin) against Staphylococci. Antibiotics were formulated as nanoemulsions and evaluated for their antimicrobial activities and cytotoxicities. Cytotoxicity of the conventional antibiotics and nanobiotics was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on rat hepatocytes. Half-maximal inhibitory concentration (IC50) was estimated from an experimentally derived dose-response curve for each concentration using GraphPad Prism software. Upon quantitative assessment of Staphylococcus biofilm formation, eighty-four isolates (66.14 %) were biofilm forming. Linezolid and doxycycline nanobiotics exhibited promising antibacterial activities. On the contrary, clindamycin nanobiotic exhibited poor antibacterial activity. Minimum biofilm inhibitory concentrations showed that 73.68 %, 45.6%, and 5.2% of isolates were sensitive to linezolid, doxycycline, and clindamycin nanobiotics, respectively. Results of this study revealed that antibiotics loaded in nanosystems had a higher antimicrobial activity and lower cytotoxicities as compared to those of conventional free antibiotics, indicating their potential therapeutic values.

scholarly journals In Vitro and In Vivo Antibacterial Activity of Gliotoxin Alone and in Combination with Antibiotics against Staphylococcus aureus

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 85
Author(s):  
Patricia Esteban ◽  
Sergio Redrado ◽  
Laura Comas ◽  
M. Pilar Domingo ◽  
M. Isabel Millán-Lou ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Antimicrobial Drugs ◽  
Hospital Acquired ◽  
Antibiotic Efficacy

Multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) is one of the major causes of hospital-acquired and community infections and pose a challenge to the human health care system. Therefore, it is important to find new drugs that show activity against these bacteria, both in monotherapy and in combination with other antimicrobial drugs. Gliotoxin (GT) is a mycotoxin produced by Aspergillus fumigatus and other fungi of the Aspergillus genus. Some evidence suggests that GT shows antimicrobial activity against S. aureus in vitro, albeit its efficacy against multidrug-resistant strains such as MRSA or vancomycin-intermediate S. aureus (VISA) strainsis not known. This work aimed to evaluate the antibiotic efficacy of GT as monotherapy or in combination with other therapeutics against MRSA in vitro and in vivo using a Caenorhabditis elegans infection model.

scholarly journals Cationic Antimicrobial Peptide LL-37 Is Effective against both Extra- and Intracellular Staphylococcus aureus

2012 ◽  
Vol 57 (3) ◽  
pp. 1283-1290 ◽  
Author(s):  
Jabeen Noore ◽  
Adly Noore ◽  
Bingyun Li
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptide ◽  
Clinical Strain ◽  
Infection Model ◽  
Intracellular Pathogens ◽  
Recurrent Infections ◽  
Bacterial Killing ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Conventional Antibiotics

ABSTRACTThe increasing resistance of bacteria to conventional antibiotics and the challenges posed by intracellular bacteria, which may be responsible for chronic and recurrent infections, have driven the need for advanced antimicrobial drugs for effective elimination of both extra- and intracellular pathogens. The purpose of this study was to determine the killing efficacy of cationic antimicrobial peptide LL-37 compared to conventional antibiotics against extra- and intracellularStaphylococcus aureus. Bacterial killing assays and an infection model of osteoblasts andS. aureuswere studied to determine the bacterial killing efficacy of LL-37 and conventional antibiotics against extra- and intracellularS. aureus. We found that LL-37 was effective in killing extracellularS. aureusat nanomolar concentrations, while lactoferricin B was effective at micromolar concentrations and doxycycline and cefazolin at millimolar concentrations. LL-37 was surprisingly more effective in killing the clinical strain than in killing an ATCC strain ofS. aureus. Moreover, LL-37 was superior to conventional antibiotics in eliminating intracellularS. aureus. The kinetic studies further revealed that LL-37 was fast in eliminating both extra- and intracellularS. aureus. Therefore, LL-37 was shown to be very potent and prompt in eliminating both extra- and intracellularS. aureusand was more effective in killing extra- and intracellularS. aureusthan commonly used conventional antibiotics. LL-37 could potentially be used to treat chronic and recurrent infections due to its effectiveness in eliminating not only extracellular but also intracellular pathogens.

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