scholarly journals A Cell-Free Screen for Bacterial Membrane Disruptors Identifies Mefloquine as a Novel Antibiotic Adjuvant

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 315
Author(s):  
Jessica Podoll ◽  
Justin Olson ◽  
Wei Wang ◽  
Xiang Wang
Keyword(s):  
Staphylococcus Aureus ◽  
High Throughput ◽  
Antibiotic Activity ◽  
Bacterial Membrane ◽  
Bacterial Membranes ◽  
Hit Rate ◽  
New Antibiotics ◽  
Lactam Antibiotic ◽  
A Cell ◽  
Bacterial Model

Antibacterial discovery efforts have lagged far behind the need for new antibiotics. An approach that has gained popularity recently is targeting bacterial phospholipid membranes. We leveraged the differences between bacterial and mammalian phospholipid compositions to develop a high-throughput screen that identifies agents that selectively disrupt bacterial membranes while leaving mammalian membranes intact. This approach was used to screen 4480 compounds representing a subset of the Maybridge HitFinderTM V.11 Collection and the Prestwick Chemical Drug Library®. The screen identified 35 “positives” (0.8% hit rate) that preferentially damage bacterial model membranes. Among these, an antimalarial compound, mefloquine, and an aminoglycoside, neomycin, were identified. Further investigation of mefloquine’s activity against Staphylococcus aureus showed that it has little antibiotic activity on its own but can alter membrane fluidity, thereby potentiating a β-lactam antibiotic, oxacillin, against both methicillin-susceptible and methicillin-resistant S. aureus. This study indicates that our cell-free screening approach is a promising platform for discovering bacterial membrane disruptors as antibacterials antibiotic adjuvants.

scholarly journals Farnesane-Type Sesquiterpenoids with Antibiotic Activity from Chiliadenus lopadusanus

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 148
Author(s):  
Marco Masi ◽  
Emanuela Roscetto ◽  
Alessio Cimmino ◽  
Maria Rosaria Catania ◽  
Giuseppe Surico ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Secondary Metabolites ◽  
Acinetobacter Baumannii ◽  
Plant Species ◽  
Antibiotic Activity ◽  
Spectroscopic Methods ◽  
Organic Extract ◽  
Aerial Parts ◽  
New Antibiotics ◽  
First Time

Chiliadenus lopadusanus Brullo is an Asteraceae plant species endemic to Lampedusa island, the largest island of the Pelage archipelago, Italy. The organic extract of its whole aerial parts, showing antibiotic activity against Staphylococcus aureus and Acinetobacter baumannii, wasfractionated employing bioguided purification procedures affording three main farnesane-type sesquiterpenoids. They were identified by spectroscopic methods (NMR and ESIMS data) as the (E)-3,7,11-trimethyldodeca-1,6,10-triene-3,9-diol, (E)-10-hydroxy-2,6,10-trimethyldodeca-2,6,11- trien-4-one and (E)-10-hydroxy-2,6,10-trimethyl-dodeca-6,11-dien-4-one, commonly named 9-hydroxynerolidol, 9-oxonerolidol, and chiliadenol B, respectively. These three sesquiterpenes, isolated for the first time from C. lopadusanus, were tested on methicillin-resistant S. aureus and A. baumannii showing antibacterial and antibiofilm activities. This plant could be used as a source to isolate secondary metabolites as potential new antibiotics.

scholarly journals Isolation of rare Genera of actinomycetes — antibiotic producers from soils using Aloe Arborescens juice

2022 ◽  
Vol 66 (9-10) ◽  
pp. 4-11
Author(s):  
O. N. Sineva
Keyword(s):  
Staphylococcus Aureus ◽  
Podzolic Soil ◽  
Micrococcus Luteus ◽  
Growth Stimulation ◽  
Antibiotic Activity ◽  
Phylogenetic Position ◽  
Genus Streptomyces ◽  
New Antibiotics ◽  
Aloe Arborescens ◽  
Layer Chromatography

The search for new antibiotics is an urgent problem due to the spread of resistance to existing antibacterial drugs in pathogenic microorganisms. Actinomycetes are producers of a large number of antibiotics used in medicine. Most antibiotics are isolated from actinomycetes of the Streptomyces genus, while rare genera of actinomycetes can be the producers of new antibiotics.The aim of the study is to investigate the effect of the biological substances complex present in aloe juice on the growth stimulation of rare genera of actinomycetes.Material and methods. Objects: samples of sod-podzolic soil and chernozem. The standard method of sowing soil suspensions on oat agar and Gause medium No. 2 was used to isolate actinomycetes. Chemotaxonomic properties were determined using the methods of ascending thin-layer chromatography on a cellulose layer. The generic identity of cultures was determined using Bergey’s manual and materials comparing the composition of cell walls of actinobacteria. DNA PCR with standard 27f and 1492r primers, as well as Sanger sequencing, were performed to study genosystematic features. Antibiotic activity was determined against the test microorganisms: Staphylococcus aureus ИНА 00985 (FDA 209P), Staphylococcus aureus ИНА 00761 (MRSA), Staphylococcus aureus ИНА 00762 (УФ- 2), Micrococcus luteus ATCC 9341, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Saccharomyces cerevisiae ИНА 01042.Results. A total of 527 actinomycete cultures were isolated from samples of sod-podzolic soil and chernozem with the addition of aloe juice; their phylogenetic position was determined. The dominant actinomycetes in the studied soil samples are the representatives of the genus Streptomyces. Bacteria of the genus Micromonospora take the second place by the number of isolated cultures. Rare genera of actinomycetes have also been identified: Nonomuraea, Streptosporangium, Nocardia, Actinomadura, Actinocorallia, Pseudonocardia, Amycolatopsis, Saccharomonospora, Saccharopolyspora, Promicromonospora, Kribbella. It was determined that the isolated cultures possess antibiotic activity against test microorganisms.Conclusion. It is advisable to use aloe juice after subjecting the leaves to biostimulation to isolate actinomycetes from the soil and identify their biodiversity.

scholarly journals Repurposing Eltrombopag for Multidrug Resistant Staphylococcus aureus Infections

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1372
Author(s):  
Hyunjung Lee ◽  
Jaehoan Lee ◽  
Juchan Hwang ◽  
Sinyoung Park ◽  
Namyoul Kim ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Repurposing ◽  
Multidrug Resistant ◽  
Aureus Strain ◽  
Infection Model ◽  
Cell Infection ◽  
Anaplastic Lymphoma ◽  
New Antibiotics ◽  
A Cell ◽  
Approved Drugs

The continuous rise of antimicrobial resistance urgently demands new therapeutic agents for human health. Drug repurposing is an attractive strategy that could significantly save time delivering new antibiotics to clinics. We screened 182 US Food and Drug Administration (FDA)-approved drugs to identify potential antibiotic candidates against Staphylococcus aureus, a major pathogenic bacterium. This screening revealed the significant antibacterial activity of three small molecule drugs against S. aureus: 1) LDK378 (Ceritinib), an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of lung cancer, 2) dronedarone HCl, an antiarrhythmic drug for the treatment of atrial fibrillation, and 3) eltrombopag, a thrombopoietin receptor agonist for the treatment of thrombocytopenia. Among these, eltrombopag showed the highest potency against not only a drug-sensitive S. aureus strain but also 55 clinical isolates including 35 methicillin-resistant S. aureus (Minimum inhibitory concentration, MIC, to inhibit 50% growth [MIC50] = 1.4−3.2 mg/L). Furthermore, we showed that eltrombopag inhibited bacterial growth in a cell infection model and reduced bacterial loads in infected mice, demonstrating its potential as a new antibiotic agent against S. aureus that can overcome current antibiotic resistance.

scholarly journals High-throughput screening and Bayesian machine learning for copper-dependent inhibitors of Staphylococcus aureus

Metallomics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 696-706 ◽  
Author(s):  
Alex G. Dalecki ◽  
Kimberley M. Zorn ◽  
Alex M. Clark ◽  
Sean Ekins ◽  
Whitney T. Narmore ◽  
...  
Keyword(s):  
Machine Learning ◽  
Staphylococcus Aureus ◽  
High Throughput ◽  
High Throughput Screening ◽  
Antibiotic Activity ◽  
Chemical Libraries ◽  
Potential Source ◽  
Bayesian Machine Learning

One potential source of new antibacterials is through probing existing chemical libraries for copper-dependent inhibitors (CDIs), i.e., molecules with antibiotic activity only in the presence of copper.

scholarly journals Role of a Sodium-Dependent Symporter Homologue in the Thermosensitivity of β-Lactam Antibiotic Resistance and Cell Wall Composition in Staphylococcus aureus

2007 ◽  
Vol 52 (2) ◽  
pp. 505-512 ◽  
Author(s):  
Krzysztof Sieradzki ◽  
Marilyn Chung ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Antibiotic Resistance ◽  
Methicillin Resistance ◽  
Homology Search ◽  
Sodium Dependent ◽  
Lactam Antibiotic ◽  
A Cell ◽  
Mrsa Strains ◽  
High Level

ABSTRACT Expression of high-level β-lactam resistance is known to be thermosensitive in many methicillin-resistant Staphylococcus aureus (MRSA) strains, including strain COL, in which the high methicillin MIC for cultures grown at 37°C (800 μg/ml) was reduced to 12 μg/ml at 42°C. COL grew faster at 42°C than at 37°C and at the higher temperature produced cell walls of abnormal composition: there was an over-representation of the monomeric muropeptide without the oligoglycine chain and an increase in the representation of multimers that contained this wall component as the donor molecule. Screening of a Tn551 insertional library for mutants, in which the high and homogenous β-lactam antibiotic resistance of strain COL is retained at 42°C, identified mutant C245, which expressed high-level methicillin resistance and produced a cell wall of normal composition independent of the temperature. The Tn551 inactivated gene was found, by homology search, to encode for a sodium-dependent symporter, homologues of which are ubiquitous in both prokaryotic and eukaryotic genomes. Inactivation of this putative symporter in several heteroresistant clinical MRSA isolates caused striking increases in the level of their β-lactam resistance.

scholarly journals Membrane-Targeting Triphenylphosphonium Functionalized Ciprofloxacin for Methicillin-Resistant Staphylococcus aureus (MRSA)

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 758
Author(s):  
Sangrim Kang ◽  
Kyoung Sunwoo ◽  
Yuna Jung ◽  
Junho K. Hur ◽  
Ki-Ho Park ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Morphological Changes ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Severe Problem ◽  
Methicillin Resistant ◽  
Bacterial Membranes ◽  
High Antibacterial Activity ◽  
New Antibiotics

Multidrug-resistant (MDR) bacteria have become a severe problem for public health. Developing new antibiotics for MDR bacteria is difficult, from inception to the clinically approved stage. Here, we have used a new approach, modification of an antibiotic, ciprofloxacin (CFX), with triphenylphosphonium (TPP, PPh3) moiety via ester- (CFX-ester-PPh3) and amide-coupling (CFX-amide-PPh3) to target bacterial membranes. In this study, we have evaluated the antibacterial activities of CFX and its derivatives against 16 species of bacteria, including MDR bacteria, using minimum inhibitory concentration (MIC) assay, morphological monitoring, and expression of resistance-related genes. TPP-conjugated CFX, CFX-ester-PPh3, and CFX-amide-PPh3 showed significantly improved antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, including MDR S. aureus (methicillin-resistant S. aureus (MRSA)) strains. The MRSA ST5 5016 strain showed high antibacterial activity, with MIC values of 11.12 µg/mL for CFX-ester-PPh3 and 2.78 µg/mL for CFX-amide-PPh3. The CFX derivatives inhibited biofilm formation in MRSA by more than 74.9% of CFX-amide-PPh3. In the sub-MIC, CFX derivatives induced significant morphological changes in MRSA, including irregular deformation and membrane disruption, accompanied by a decrease in the level of resistance-related gene expression. With these promising results, this method is very likely to combat MDR bacteria through a simple TPP moiety modification of known antibiotics, which can be readily prepared at clinical sites.

scholarly journals CdSe QD Biosynthesis in Yeast Using Tryptone-Enriched Media and Their Conjugation with a Peptide Hecate for Bacterial Detection and Killing

Nanomaterials ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 1463 ◽  
Author(s):  
Vishma Pratap Sur ◽  
Marketa Kominkova ◽  
Zaneta Buchtova ◽  
Kristyna Dolezelikova ◽  
Ondrej Zitka ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Synthesis Process ◽  
Synthesis Methods ◽  
Bacterial Cells ◽  
Cdse Qds ◽  
Yeast Saccharomyces Cerevisiae ◽  
Shape Distribution ◽  
Transmission Electron ◽  
A Cell ◽  
Physical And Chemical

The physical and chemical synthesis methods of quantum dots (QDs) are generally unfavorable for biological applications. To overcome this limitation, the development of a novel “green” route to produce highly-fluorescent CdSe QDs constitutes a promising substitute approach. In the present work, CdSe QDs were biosynthesized in yeast Saccharomyces cerevisiae using a novel method, where we showed for the first time that the concentration of tryptone highly affects the synthesis process. The optimum concentration of tryptone was found to be 25 g/L for the highest yield. Different methods were used to optimize the QD extraction from yeast, and the best method was found to be by denaturation at 80 °C along with an ultrasound needle. Multiple physical characterizations including transmission electron microscopy (TEM), dynamic light scattering (DLS), energy-dispersive X-ray spectroscopy (EDX), and spectrophotometry confirmed the optical features size and shape distribution of the QDs. We showed that the novel conjugate of the CdSe QDs and a cell-penetrating peptide (hecate) can detect bacterial cells very efficiently under a fluorescent microscope. The conjugate also showed strong antibacterial activity against vancomycin-resistant Staphylococcus aureus (VRSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli, which may help us to cope with the problem of rising antibiotic resistance.

scholarly journals Evaluation of a System to Screen for Stimulators of Non-Specific DNA Nicking by HIV-1 Integrase: Application to a Library of 50,000 Compounds

2011 ◽  
Vol 22 (2) ◽  
pp. 67-74 ◽  
Author(s):  
Malgorzata Sudol ◽  
Jennifer L Fritz ◽  
Melissa Tran ◽  
Gavin P Robertson ◽  
Julie B Ealy ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Solution Phase ◽  
The Novel ◽  
Endonuclease Activity ◽  
Viral Dna ◽  
Hit Rate ◽  
Dna Nicking ◽  
Hiv 1 ◽  
Stimulation Of

Background: In addition to activities needed to catalyse integration, retroviral integrases exhibit non-specific endonuclease activity that is enhanced by certain small compounds, suggesting that integrase could be stimulated to damage viral DNA before integration occurs. Methods: A non-radioactive, plate-based, solution phase, fluorescence assay was used to screen a library of 50,080 drug-like chemicals for stimulation of non-specific DNA nicking by HIV-1 integrase. Results: A semi-automated workflow was established and primary hits were readily identified from a graphic output. Overall, 0.6% of the chemicals caused a large increase in fluorescence (the primary hit rate) without also having visible colour that could have artifactually caused this result. None of the potential stimulators from this moderate-size library, however, passed a secondary test that included an inactive integrase mutant that assessed whether the increased fluorescence depended on the endonuclease activity of integrase. Conclusions: This first attempt at identifying integrase stimulator compounds establishes the necessary logistics and workflow required. The results from this study should encourage larger scale high-throughput screening to advance the novel antiviral strategy of stimulating integrase to damage retroviral DNA.

scholarly journals On the Wireless Microwave Sensing of Bacterial Membrane Potential in Microfluidic-Actuated Platforms

Sensors ◽  
2021 ◽  
Vol 21 (10) ◽  
pp. 3420
Author(s):  
Marc Jofre ◽  
Lluís Jofre ◽  
Luis Jofre-Roca
Keyword(s):  
Membrane Potential ◽  
Living Cells ◽  
Membrane Potentials ◽  
Electromagnetic Properties ◽  
Bacterial Membrane ◽  
Microfluidic Platforms ◽  
Bacterial Membranes ◽  
Wireless Monitoring ◽  
Bacterial Dynamics ◽  
Engineered Systems

The investigation of the electromagnetic properties of biological particles in microfluidic platforms may enable microwave wireless monitoring and interaction with the functional activity of microorganisms. Of high relevance are the action and membrane potentials as they are some of the most important parameters of living cells. In particular, the complex mechanisms of a cell’s action potential are comparable to the dynamics of bacterial membranes, and consequently focusing on the latter provides a simplified framework for advancing the current techniques and knowledge of general bacterial dynamics. In this work, we provide a theoretical analysis and experimental results on the microwave detection of microorganisms within a microfluidic-based platform for sensing the membrane potential of bacteria. The results further advance the state of microwave bacteria sensing and microfluidic control and their implications for measuring and interacting with cells and their membrane potentials, which is of great importance for developing new biotechnologically engineered systems and solutions.

scholarly journals Real-time imaging of cellular forces using optical interference

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrew T. Meek ◽  
Nils M. Kronenberg ◽  
Andrew Morton ◽  
Philipp Liehm ◽  
Jan Murawski ◽  
...  
Keyword(s):  
Cell Culture ◽  
Real Time ◽  
High Throughput ◽  
Mechanical Activity ◽  
Dynamic Processes ◽  
Imaging Method ◽  
Neonatal Cardiomyocytes ◽  
A Cell ◽  
Cellular Forces ◽  
Time Acquisition

AbstractImportant dynamic processes in mechanobiology remain elusive due to a lack of tools to image the small cellular forces at play with sufficient speed and throughput. Here, we introduce a fast, interference-based force imaging method that uses the illumination of an elastic deformable microcavity with two rapidly alternating wavelengths to map forces. We show real-time acquisition and processing of data, obtain images of mechanical activity while scanning across a cell culture, and investigate sub-second fluctuations of the piconewton forces exerted by macrophage podosomes. We also demonstrate force imaging of beating neonatal cardiomyocytes at 100 fps which reveals mechanical aspects of spontaneous oscillatory contraction waves in between the main contraction cycles. These examples illustrate the wider potential of our technique for monitoring cellular forces with high throughput and excellent temporal resolution.

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