scholarly journals Multi-target mode of action of silver against Staphylococcus aureus endows it with capability to combat antibiotic resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haibo Wang ◽  
Minji Wang ◽  
Xiaohan Xu ◽  
Peng Gao ◽  
Zeling Xu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mode Of Action ◽  
Molecular Targets ◽  
Antibiotic Resistant ◽  
X Ray ◽  
X Ray Crystallography ◽  
Phosphogluconate Dehydrogenase ◽  
Target Mode ◽  
Conventional Antibiotics ◽  
Rapid Emergence

AbstractThe rapid emergence of drug resistant Staphylococcus aureus (S. aureus) poses a serious threat to public health globally. Silver (Ag)-based antimicrobials are promising to combat antibiotic resistant S. aureus, yet their molecular targets are largely elusive. Herein, we separate and identify 38 authentic Ag+-binding proteins in S. aureus at the whole-cell scale. We then capture the molecular snapshot on the dynamic action of Ag+ against S. aureus and further validate that Ag+ could inhibit a key target 6-phosphogluconate dehydrogenase through binding to catalytic His185 by X-ray crystallography. Significantly, the multi-target mode of action of Ag+ (and nanosilver) endows its sustainable antimicrobial efficacy, leading to enhanced efficacy of conventional antibiotics and resensitization of MRSA to antibiotics. Our study resolves the long-standing question of the molecular targets of silver in S. aureus and offers insights into the sustainable bacterial susceptibility of silver, providing a potential approach for combating antimicrobial resistance.

Preparation, Characterisation, Crystal Structure and Antibacterial Activity of two Bis-Schiff Bases Containing a Piperazine Ring

2018 ◽  
Vol 42 (10) ◽  
pp. 512-514
Author(s):  
Rui-bo Xu ◽  
Xiao-tian Yang ◽  
Hai-nan Li ◽  
Peng-cheng Zhao ◽  
Jiao-jiao Li ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Bacillus Subtilis ◽  
Schiff Bases ◽  
Piperazine Ring ◽  
X Ray ◽  
X Ray Crystallography ◽  
Good Antibacterial Activity

Two new bis-Schiff bases containing a piperazine ring, N,N‘-bis(4-chlorobenzylidene)- and N,N‘-bis(4-cyanobenzylidene)-1,4-bis(3-aminopropyl)piperazine, were prepared by the reaction of N,N‘-bis(3-aminopropyl)piperazine with 4-chloro- and 4-cyanobenzaldehyde, respectively. The dichloro compound was fully identified by X-ray crystallography and it exhibited good antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis.

scholarly journals A Small Membrane Stabilizing Protein Critical to the Pathogenicity of Staphylococcus aureus

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Seána Duggan ◽  
Maisem Laabei ◽  
Alaa Abdulaziz Alnahari ◽  
Eóin C. O’Brien ◽  
Keenan A. Lacey ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Iron Homeostasis ◽  
Control Strategies ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Promising Target ◽  
Significant Impairment ◽  
The Stability ◽  
Conventional Antibiotics ◽  
And Control

ABSTRACT Staphylococcus aureus is a major human pathogen, and the emergence of antibiotic-resistant strains is making all types of S. aureus infections more challenging to treat. With a pressing need to develop alternative control strategies to use alongside or in place of conventional antibiotics, one approach is the targeting of established virulence factors. However, attempts at this have had little success to date, suggesting that we need to better understand how this pathogen causes disease if effective targets are to be identified. To address this, using a functional genomics approach, we have identified a small membrane-bound protein that we have called MspA. Inactivation of this protein results in the loss of the ability of S. aureus to secrete cytolytic toxins, protect itself from several aspects of the human innate immune system, and control its iron homeostasis. These changes appear to be mediated through a change in the stability of the bacterial membrane as a consequence of iron toxicity. These pleiotropic effects on the ability of the pathogen to interact with its host result in significant impairment in the ability of S. aureus to cause infection in both a subcutaneous and sepsis model of infection. Given the scale of the effect the inactivation of MspA causes, it represents a unique and promising target for the development of a novel therapeutic approach.

scholarly journals Structural insight into the Staphylococcus aureus ATP-driven exporter of virulent peptide toxins

2020 ◽  
Vol 6 (40) ◽  
pp. eabb8219
Author(s):  
N. Zeytuni ◽  
S. W. Dickey ◽  
J. Hu ◽  
H. T. Chou ◽  
L. J. Worrall ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Bound State ◽  
Broad Spectrum Antibiotic ◽  
X Ray ◽  
X Ray Crystallography ◽  
Open Conformation ◽  
Mechanistic Insight ◽  
Cytolytic Peptides ◽  
Peptide Toxins ◽  
Insight Into

Staphylococcus aureus is a major human pathogen that has acquired alarming broad-spectrum antibiotic resistance. One group of secreted toxins with key roles during infection is the phenol-soluble modulins (PSMs). PSMs are amphipathic, membrane-destructive cytolytic peptides that are exported to the host-cell environment by a designated adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporter, the PSM transporter (PmtABCD). Here, we demonstrate that the minimal Pmt unit necessary for PSM export is PmtCD and provide its first atomic characterization by single-particle cryo-EM and x-ray crystallography. We have captured the transporter in the ATP-bound state at near atomic resolution, revealing a type II ABC exporter fold, with an additional cytosolic domain. Comparison to a lower-resolution nucleotide-free map displaying an “open” conformation and putative hydrophobic inner chamber of a size able to accommodate the binding of two PSM peptides provides mechanistic insight and sets the foundation for therapeutic design.

scholarly journals The canal inclusion complex of allicin with carbamide: Preparation, characterization and microbiological investigation

2005 ◽  
Vol 11 (2) ◽  
pp. 69-73 ◽  
Author(s):  
Vesna Nikolic ◽  
Mihajlo Stankovic ◽  
Ljubisa Nikolic ◽  
Dragan Cvetkovic ◽  
Agnes Kapor ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Candida Albicans ◽  
Inclusion Complex ◽  
Microbiological Investigation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Bacteria And Fungi ◽  
Growth Of Bacteria

The carbamide:allicin canal inclusion complex was prepared in the solid state. The structure of the complex obtained was characterized by x-ray crystallography, infrared spectroscopy and thermogravimetric analysis. The microbiological activities of the inclusion complex and allicin were investigated and compared with respect to fungi (Candida albicans ATCC 10231 and Aspergillus niger ATCC 16404) and bacteria (Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 9027). It was found that the inclusion complex inhibited the growth of bacteria and fungi for a longer period than allicin in the free state.

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 Structure and Stoichiometry of the Ton Molecular Motor

2020 ◽  
Vol 21 (2) ◽  
pp. 375 ◽  
Author(s):  
Herve Celia ◽  
Nicholas Noinaj ◽  
Susan K Buchanan
Keyword(s):  
Outer Membrane ◽  
Mode Of Action ◽  
Molecular Motor ◽  
Proton Gradient ◽  
Gram Negative Bacteria ◽  
Periplasmic Space ◽  
Inner Membrane ◽  
Gram Negative ◽  
X Ray ◽  
X Ray Crystallography

The Ton complex is a molecular motor that uses the proton gradient at the inner membrane of Gram-negative bacteria to generate force and movement, which are transmitted to transporters at the outer membrane, allowing the entry of nutrients into the periplasmic space. Despite decades of investigation and the recent flurry of structures being reported by X-ray crystallography and cryoEM, the mode of action of the Ton molecular motor has remained elusive, and the precise stoichiometry of its subunits is still a matter of debate. This review summarizes the latest findings on the Ton system by presenting the recently reported structures and related reports on the stoichiometry of the fully assembled complex.

Antibiotic Resistance, the Horrendous Consequences of Bacterial Sex

2021 ◽  
pp. 111-116
Author(s):  
Thomas E. Schindler
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Methicillin Resistant ◽  
Postwar Japan ◽  
Resistant Genes ◽  
Rapid Emergence ◽  
Multiple Antibiotics

This chapter reviews how bacterial sex explains the rapid emergence of superbugs that are resistant to multiple antibiotics, the so-called MDR pathogens. Millions of years before humans evolved, bacteria invented antibiotics and the defensive molecules that make some bacteria resistant to an antibiotic. Therefore, antibiotic resistant genes pre-exist in many bacterial strains, literally lying in wait to emerge in superbugs. In postwar Japan, bacteriologists discovered the first MDR pathogens during dysentery outbreaks. Researchers demonstrated that the genes for resistance to several antibiotics were transferred by bacterial sex—from normal flora to the dysentery pathogens—all together and “at one stroke.” Methicillin was intentionally designed to treat penicillin-resistant infections. Only three years after its introduction of, hospitals began to find methicillin-resistant Staphylococcus aureus (MRSA). Gerard Wright coined the term resistome to signify “the global collection of resistance genes that have been readily available to pathogens for millennia.”

SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance

2021 ◽  
Author(s):  
Chieh-Hsien Lu ◽  
Chung-Wai Shiau ◽  
Yung-Chi Chang ◽  
Hsiu-Ni Kung ◽  
Jui-Ching Wu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mode Of Action ◽  
Cytoplasmic Membrane ◽  
Resistance Development ◽  
Antibiotic Resistant ◽  
Atp Production ◽  
The Past ◽  
Ht 29

Abstract Objectives In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound. Methods The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry. Results SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters. Conclusions Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.

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 A polymerisation-associated conformational switch in FtsZ that enables treadmilling

2016 ◽  
Author(s):  
James M. Wagstaff ◽  
Matthew Tsim ◽  
María A. Oliva ◽  
Alba García-Sanchez ◽  
Danguole Kureisaite-Ciziene ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Division ◽  
Bacterial Cell Division ◽  
Conformational Switch ◽  
Septal Wall ◽  
Crystal Forms ◽  
X Ray ◽  
E Coli ◽  
X Ray Crystallography ◽  
Filament Assembly

AbstractBacterial cell division in many organisms involves a constricting cytokinetic ring that is orchestrated by the tubulin-like protein FtsZ. FtsZ forms dynamic filaments close to the membrane at the site of division that have recently been shown to treadmill around the division ring, guiding septal wall synthesis.Here, using X-ray crystallography ofStaphylococcus aureusSaFtsZ we reveal how an FtsZ can adopt two functionally distinct conformations, open and closed. The open form is found in SaFtsZ filaments formed in crystals and also in soluble filaments ofE. coliFtsZ as deduced by cryoEM. The closed form is found within several crystal forms of two non-polymerising SaFtsZ mutants and corresponds to many previous FtsZ structures from other organisms.We argue that FtsZ undergoes a polymerisation-associated conformational switch. We show that such a switch provides explanations for both how treadmilling may occur within a single-stranded filament, and why filament assembly is cooperative.

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