scholarly journals Unveiling the Membrane and Cell Wall Action of Antimicrobial Cyclic Lipopeptides: Modulation of the Spectrum of Activity

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2180
Author(s):  
Roser Segovia ◽  
Judith Solé ◽  
Ana Maria Marqués ◽  
Yolanda Cajal ◽  
Francesc Rabanal
Keyword(s):  
Membrane Integrity ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Membrane Function ◽  
Gram Negative ◽  
Transmission Electron ◽  
New Antibiotics ◽  
Public Health Challenge ◽  
Selective Antibiotics

Antibiotic resistance is a major public health challenge, and Gram-negative multidrug-resistant bacteria are particularly dangerous. The threat of running out of active molecules is accelerated by the extensive use of antibiotics in the context of the COVID-19 pandemic, and new antibiotics are urgently needed. Colistin and polymyxin B are natural antibiotics considered as last resort drugs for multi-resistant infections, but their use is limited because of neuro- and nephrotoxicity. We previously reported a series of synthetic analogues inspired in natural polymyxins with a flexible scaffold that allows multiple modifications to improve activity and reduce toxicity. In this work, we focus on modifications in the hydrophobic domains, describing analogues that broaden or narrow the spectrum of activity including both Gram-positive and Gram-negative bacteria, with MICs in the low µM range and low hemolytic activity. Using biophysical methods, we explore the interaction of the new molecules with model membranes that mimic the bacterial inner and outer membranes, finding a selective effect on anionic membranes and a mechanism of action based on the alteration of membrane function. Transmission electron microscopy observation confirms that polymyxin analogues kill microbial cells primarily by damaging membrane integrity. Redistribution of the hydrophobicity within the polymyxin molecule seems a plausible approach for the design and development of safer and more selective antibiotics.

scholarly journals Ts2631 Endolysin from the Extremophilic Thermus scotoductus Bacteriophage vB_Tsc2631 as an Antimicrobial Agent against Gram-Negative Multidrug-Resistant Bacteria

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 657 ◽  
Author(s):  
Magdalena Plotka ◽  
Malgorzata Kapusta ◽  
Sebastian Dorawa ◽  
Anna-Karina Kaczorowska ◽  
Tadeusz Kaczorowski
Keyword(s):  
Metal Ion ◽  
Ethylenediaminetetraacetic Acid ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative ◽  
Log Reduction ◽  
Carbapenem Resistant ◽  
Heat Stable ◽  
Transmission Electron

Bacteria that thrive in extreme conditions and the bacteriophages that infect them are sources of valuable enzymes resistant to denaturation at high temperatures. Many of these heat-stable proteins are useful for biotechnological applications; nevertheless, none have been utilized as antibacterial agents. Here, we demonstrate the bactericidal potential of Ts2631 endolysin from the extremophilic bacteriophage vB_Tsc2631, which infects Thermus scotoductus, against the alarming multidrug-resistant clinical strains of Acinetobacter baumannii, Pseudomonas aeruginosa and pathogens from the Enterobacteriaceae family. A 2–3.7 log reduction in the bacterial load was observed in antibacterial tests against A. baumannii and P. aeruginosa after 1.5 h. The Ts2631 activity was further enhanced by ethylenediaminetetraacetic acid (EDTA), a metal ion chelator (4.2 log reduction in carbapenem-resistant A. baumannii) and, to a lesser extent, by malic acid and citric acid (2.9 and 3.3 log reductions, respectively). The EDTA/Ts2631 combination reduced all pathogens of the Enterobacteriaceae family, particularly multidrug-resistant Citrobacter braakii, to levels below the detection limit (>6 log); these results indicate that Ts2631 endolysin could be useful to combat Gram-negative pathogens. The investigation of A. baumannii cells treated with Ts2631 endolysin variants under transmission electron and fluorescence microscopy demonstrates that the intrinsic antibacterial activity of Ts2631 endolysin is dependent on the presence of its N-terminal tail.

scholarly journals Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5643
Author(s):  
Bee-Ha Gan ◽  
Xingguang Cai ◽  
Sacha Javor ◽  
Thilo Köhler ◽  
Jean-Louis Reymond
Keyword(s):  
Synergistic Effect ◽  
Propidium Iodide ◽  
Synergistic Effects ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Outer Membranes ◽  
New Antibiotics

There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active against such bacteria and often act by destabilizing membranes, a mechanism that can also be used to permeabilize bacteria to other antibiotics, resulting in synergistic effects. We recently showed that G3KL, an AMP with a multibranched dendritic topology of the peptide chain, permeabilizes the inner and outer membranes of Gram-negative bacteria including multidrug-resistant strains, leading to efficient bacterial killing. Here, we show that permeabilization of the outer and inner membranes of Pseudomonas aeruginosa by G3KL, initially detected using the DNA-binding fluorogenic dye propidium iodide (PI), also leads to a synergistic effect between G3KL and PI in this bacterium. We also identify a synergistic effect between G3KL and six different antibiotics against the Gram-negative Klebsiella pneumoniae, against which G3KL is inactive.

scholarly journals Comparison of four phenotypic methods for detection of metallo-β-lactamase-producing Gram-negative bacteria in rural teaching hospital

2017 ◽  
Vol 9 (02) ◽  
pp. 081-083 ◽  
Author(s):  
Chinjal A. Panchal ◽  
Sweta Sunil Oza ◽  
Sanjay J. Mehta
Keyword(s):  
Antibiotic Sensitivity ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
Extended Spectrum Beta Lactamases ◽  
Synergy Test ◽  
Phenotypic Methods

Abstract CONTEXT: Metallo-β-lactamase (MBL)-producing bacteria lead to resistance to carbapenem an antibiotic that used as the last resort for treatment of multidrug-resistant bacteria, extended spectrum beta-lactamases, and AmpC β-lactamase-producing Gram-negative bacteria (GNB). The emergence of MBL-producing GNB is challenge to microbiology laboratories because there are no standardized guidelines available to detect them. The aim of this study was to compare four phenotypic methods to detect MBL production in GNB and to determine antibiotic sensitivity of MBL-producing isolates. MATERIALS AND METHODS: A total of 107 clinical isolates of GNB were tested for MBL production. Imipenem (IPM)-resistant GNB were taken as positive for MBL screening. MBL detection was done using ethylene diamine tetra acetic acid (EDTA) as MBL inhibitor. Four phenotypic methods were evaluated: (1) Combined disk synergy test (CDST) with 0.5M EDTA (CDST-0.5 M EDTA), (2) CDST with 0.1 M EDTA (CDST-0.1 M EDTA), (3) double-disk synergy test (DDST) with 0.5M EDTA (DDST-0.5 M EDTA), and (4) DDST with 0.1 M EDTA (DDST-0.1 M EDTA). RESULTS: Out of 107 GNB, 30 were resistant to IPM considered as screening positive. Out of 30, 21 (70%) isolates were MBL positive by CDST-0.1 M EDTA, 19 (63.33%) by CDST-0.5M EDTA, 17 (56.67%) by DDST-0.1 M EDTA, and 16 (53.33%) by DDST-0.5M EDTA. All MBL-producing Gram-negative Bacilli were resistant to ampicillin/sulbactam. Polymyxin B was found to be the most sensitive drug. CONCLUSION: CDST-0.1 M EDTA is the most sensitive method MBL detection. The detection of MBL-producing GNB is very important to control spread of the resistance.

scholarly journals Battacin (Octapeptin B5), a New Cyclic Lipopeptide Antibiotic from Paenibacillus tianmuensis Active against Multidrug-Resistant Gram-Negative Bacteria

2011 ◽  
Vol 56 (3) ◽  
pp. 1458-1465 ◽  
Author(s):  
Chao-Dong Qian ◽  
Xue-Chang Wu ◽  
Yi Teng ◽  
Wen-Peng Zhao ◽  
Ou Li ◽  
...  
Keyword(s):  
Polymyxin B ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Lipopeptide Antibiotic

ABSTRACTHospital-acquired infections caused by drug-resistant bacteria are a significant challenge to patient safety. Numerous clinical isolates resistant to almost all commercially available antibiotics have emerged. Thus, novel antimicrobial agents, specifically those for multidrug-resistant Gram-negative bacteria, are urgently needed. In the current study, we report the isolation, structure elucidation, and preliminary biological characterization of a new cationic lipopeptide antibiotic, battacin or octapeptin B5, produced from aPaenibacillus tianmuensissoil isolate. Battacin kills bacteriain vitroand has potent activity against Gram-negative bacteria, including multidrug-resistant and extremely drug-resistant clinical isolates. Hospital strains ofEscherichia coliandPseudomonas aeruginosaare the pathogens most sensitive to battacin, with MICs of 2 to 4 μg/ml. The ability of battacin to disrupt the outer membrane of Gram-negative bacteria is comparable to that of polymyxin B, the last-line therapy for infections caused by antibiotic-resistant Gram-negative bacteria. However, the capacity of battacin to permeate bacterial plasma membranes is less extensive than that of polymyxin B. The bactericidal kinetics of battacin correlate with the depolarization of the cell membrane, suggesting that battacin kills bacteria by disrupting the cytoplasmic membrane. Other studies indicate that battacin is less acutely toxic than polymyxin B and has potentin vivobiological activity againstE. coli. Based on the findings of the current study, battacin may be considered a potential therapeutic agent for the treatment of infections caused by antibiotic-resistant Gram-negative bacteria.

scholarly journals In vitro biological activity of Hydroclathrus clathratus and its use as an extracellular bioreductant for silver nanoparticle formation

2020 ◽  
Vol 9 (1) ◽  
pp. 416-428 ◽  
Author(s):  
Raghad R. Alzahrani ◽  
Manal M. Alkhulaifi ◽  
Nouf M. Al-Enazi
Keyword(s):  
Biological Activity ◽  
Unsaturated Fatty Acids ◽  
Multidrug Resistant ◽  
Chemical Components ◽  
Resistant Bacteria ◽  
Transmission Electron ◽  
Hydroclathrus Clathratus ◽  
Adaptive Nature ◽  
First Time

AbstractThe adaptive nature of algae results in producing unique chemical components that are gaining attention due to their efficiency in many fields and abundance. In this study, we screened the phytochemicals from the brown alga Hydroclathrus clathratus and tested its ability to produce silver nanoparticles (AgNPs) extracellularly for the first time. Lastly, we investigated its biological activity against a variety of bacteria. The biosynthesized nanoparticles were characterized by UV-visible spectroscopy, Fourier-transform infrared spectroscopy, dynamic light scattering, transmission electron microscopy, and energy-dispersive spectroscopy. The biological efficacy of AgNPs was tested against eighteen different bacteria, including seven multidrug-resistant bacteria. Phytochemical screening of the alga revealed the presence of saturated and unsaturated fatty acids, sugars, carboxylic acid derivatives, triterpenoids, steroids, and other components. Formed AgNPs were stable and ranged in size between 7 and 83 nm and presented a variety of shapes. Acinetobacter baumannii, Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), and MDR A. baumannii were the most affected among the bacteria. The biofilm formation and development assay presented a noteworthy activity against MRSA, with an inhibition percentage of 99%. Acknowledging the future of nano-antibiotics encourages scientists to explore and enhance their potency, notably if they were obtained using green, rapid, and efficient methods.

scholarly journals Prevalence of multidrug-resistant and extended-spectrum beta-lactamase producing Gram-negative isolates from clinical samples in a tertiary care hospital of Nepal

2021 ◽  
Vol 49 (1) ◽  
Author(s):  
Aryatara Shilpakar ◽  
Mehraj Ansari ◽  
Kul Raj Rai ◽  
Ganesh Rai ◽  
Shiba Kumar Rai
Keyword(s):  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Confirmatory Test ◽  
Clinical Samples ◽  
Care Hospital ◽  
Gram Negative ◽  
Extended Spectrum ◽  
Esbl Producers

Abstract Background The existence of multidrug-resistant organisms, including extended-spectrum beta-lactamases (ESBLs), is on rise across the globe and is becoming a severe problem. Knowledge of the prevalence and antibiogram profile of such isolates is essential to develop an appropriate treatment methodology. This study aimed to study the prevalence of Gram-negative isolates exhibiting ESBL at a tertiary care hospital and study their antibiogram profile. Methods A cross-sectional study was conducted at Shahid Gangalal National Heart Centre, Kathmandu, Nepal, from June 2018 to November 2018. A total of 770 clinical samples were collected and identified using the conventional biochemical tests following the Clinical and Laboratory Standard Institute (CLSI) guidelines. Antimicrobial susceptibility testing (AST) was performed using the standardized Kirby-Bauer disk diffusion method. The screening test for ESBL producers was performed as recommended by the CLSI and the confirmatory test was performed phenotypically using the E-test. Results Out of the 92 isolates, 84 (91.3%) were multidrug-resistant, and 47 (51.1%) were found to be potential ESBL producers. Of these, 16 isolates were confirmed ESBL producers by the E-test. Escherichia coli and Klebsiella pneumoniae were the predominant isolates and were also the major ESBL producers. Besides polymyxin B (100% sensitive), meropenem and imipenem showed high efficacy against the ESBL producers. Conclusion Multidrug resistance was very high; however, ESBL production was low. Polymyxin B and carbapenems are the choice of drugs against ESBL producers but should be used only as the last line drugs.

scholarly journals The Synergistic Effect of Biosynthesized Silver Nanoparticles and Phage ZCSE2 as a Novel Approach to Combat Multidrug-Resistant Salmonella enterica

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 678
Author(s):  
Abdallah S. Abdelsattar ◽  
Rana Nofal ◽  
Salsabil Makky ◽  
Anan Safwat ◽  
Amera Taha ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Color Change ◽  
Antibacterial Properties ◽  
Multidrug Resistant ◽  
Inhibitory Effect ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Mortality And Morbidity ◽  
Novel Approach ◽  
Transmission Electron

The emergence and evolution of antibiotic-resistant bacteria is considered a public health concern. Salmonella is one of the most common pathogens that cause high mortality and morbidity rates in humans, animals, and poultry annually. In this work, we developed a combination of silver nanoparticles (AgNPs) with bacteriophage (phage) as an antimicrobial agent to control microbial growth. The synthesized AgNPs with propolis were characterized by testing their color change from transparent to deep brown by transmission electron microscopy (TEM) and Fourier-Transform Infrared Spectroscopy (FTIR). The phage ZCSE2 was found to be stable when combined with AgNPs. Both minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were evaluated for AgNPs, phage, and their combination. The results indicated that MIC and MBC values were equal to 23 µg/mL against Salmonella bacteria at a concentration of 107 CFU/mL. The combination of 0.4× MIC from AgNPs and phage with Multiplicity of Infection (MOI) 0.1 showed an inhibitory effect. This combination of AgNPs and phage offers a prospect of nanoparticles with significantly enhanced antibacterial properties and therapeutic performance.

scholarly journals Amphipathic Peptide Antibiotics with Potent Activity against Multidrug-Resistant Pathogens

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 438
Author(s):  
Jingru Shi ◽  
Chen Chen ◽  
Dejuan Wang ◽  
Ziwen Tong ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Multidrug Resistant ◽  
Peptide Antibiotics ◽  
Biofilm Inhibition ◽  
Amphipathic Peptide ◽  
Host Defense Peptides ◽  
Gram Negative ◽  
Wide Range ◽  
New Antibiotics ◽  
Low Toxicity

The emergence and prevalence of multidrug-resistant (MDR) bacteria have posed a serious threat to public health. Of particular concern are methicillin-resistant Staphylococcus aureus (MRSA) and blaNDM, mcr-1 and tet(X)-positive Gram-negative pathogens. The fact that few new antibiotics have been approved in recent years exacerbates this global crisis, thus, new alternatives are urgently needed. Antimicrobial peptides (AMPs) originated from host defense peptides with a wide range of sources and multiple functions, are less prone to achieve resistance. All these characteristics laid the foundation for AMPs to become potential antibiotic candidates. In this study, we revealed that peptide WW307 displayed potent antibacterial and bactericidal activity against MDR bacteria, including MRSA and Gram-negative bacteria carrying blaNDM-5, mcr-1 or tet(X4). In addition, WW307 exhibited great biofilm inhibition and eradication activity. Safety and stability experiments showed that WW307 had a strong resistance against various physiological conditions and displayed relatively low toxicity. Mechanistic experiments showed that WW307 resulted in membrane damage by selectively targeting bacterial membrane-specific components, including lipopolysaccharide (LPS), phosphatidylglycerol (PG), and cardiolipin (CL). Moreover, WW307 dissipated membrane potential and triggered the production of reactive oxygen species (ROS). Collectively, these results demonstrated that WW307 represents a promising candidate for combating MDR pathogens.

scholarly journals In vitro activity of antimicrobial peptide CDP-B11 alone and in combination with colistin against colistin-resistant and multidrug-resistant Escherichia coli

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaitlin S. Witherell ◽  
Jason Price ◽  
Ashok D. Bandaranayake ◽  
James Olson ◽  
Douglas R. Call
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Peptide ◽  
Membrane Integrity ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
E Coli ◽  
Minimal Media

AbstractMultidrug-resistant bacteria are a growing global concern, and with increasingly prevalent resistance to last line antibiotics such as colistin, it is imperative that alternative treatment options are identified. Herein we investigated the mechanism of action of a novel antimicrobial peptide (CDP-B11) and its effectiveness against multidrug-resistant bacteria including Escherichia coli #0346, which harbors multiple antibiotic-resistance genes, including mobilized colistin resistance gene (mcr-1). Bacterial membrane potential and membrane integrity assays, measured by flow cytometry, were used to test membrane disruption. Bacterial growth inhibition assays and time to kill assays measured the effectiveness of CDP-B11 alone and in combination with colistin against E. coli #0346 and other bacteria. Hemolysis assays were used to quantify the hemolytic effects of CDP-B11 alone and in combination with colistin. Findings show CDP-B11 disrupts the outer membrane of E. coli #0346. CDP-B11 with colistin inhibits the growth of E. coli #0346 at ≥ 10× lower colistin concentrations compared to colistin alone in Mueller–Hinton media and M9 media. Growth is significantly inhibited in other clinically relevant strains, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. In rich media and minimal media, the drug combination kills bacteria at a lower colistin concentration (1.25 μg/mL) compared to colistin alone (2.5 μg/mL). In minimal media, the combination is bactericidal with killing accelerated by up to 2 h compared to colistin alone. Importantly, no significant red blood hemolysis is evident for CDP-B11 alone or in combination with colistin. The characteristics of CDP-B11 presented here indicate that it can be used as a potential monotherapy or as combination therapy with colistin for the treatment of multidrug-resistant infections, including colistin-resistant infections.

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