Proteome reactivity profiling for the discrimination of pathogenic bacteria

2014 ◽  
Vol 50 (33) ◽  
pp. 4347-4350 ◽  
Author(s):  
Jun-Seok Lee ◽  
Young-Hwa Yoo ◽  
Jihye Kang ◽  
Won Seok Han ◽  
Jin Kak Lee ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Benzyl Halide

Diverse proteome reactivity profiles were obtained using small-molecule electrophiles. Here, we report the first proteome reactivity signature-based discrimination of 11 bacteria. Perfect differentiation of 11 bacteria can be achieved using 2 benzyl-halide probes.

scholarly journals Eradication of Intracellular Salmonellaenterica Serovar Typhimurium with a Small-Molecule, Host Cell-Directed Agent

2009 ◽  
Vol 53 (12) ◽  
pp. 5236-5244 ◽  
Author(s):  
Hao-Chieh Chiu ◽  
Samuel K. Kulp ◽  
Shilpa Soni ◽  
Dasheng Wang ◽  
John S. Gunn ◽  
...  
Keyword(s):  
Host Cell ◽  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Intracellular Survival ◽  
Resistant Bacteria ◽  
Intracellular Bacteria ◽  
Akt Kinase ◽  
Antibiotic Resistant ◽  
Serovar Typhimurium ◽  
Host Cell Factors

ABSTRACTEradication of intracellular pathogenic bacteria with host-directed chemical agents has been an anticipated innovation in the treatment of antibiotic-resistant bacteria. We previously synthesized and characterized a novel small-molecule agent, AR-12, that induces autophagy and inhibits the Akt kinase in cancer cells. As both autophagy and the Akt kinase have been shown recently to play roles in the intracellular survival of several intracellular bacteria, includingSalmonellaentericaserovar Typhimurium, we investigated the effect of AR-12 on the intracellular survival ofSalmonellaserovar Typhimurium in macrophages. Our results show that AR-12 induces autophagy in macrophages, as indicated by increased autophagosome formation, and potently inhibits the survival of serovar Typhimurium in macrophages in association with increased colocalization of intracellular bacteria with autophagosomes. Intracellular bacterial growth was partially rescued in the presence of AR-12 by the short hairpin RNA-mediated knockdown of Beclin-1 or Atg7 in macrophages. Moreover, AR-12 inhibits Akt kinase activity in infected macrophages, which we show to be important for its antibacterial effect as the enforced expression of constitutively activated Akt1 in these cells reverses the AR-12-induced inhibition of intracellular serovar Typhimurium survival. Finally, oral administration of AR-12 at 2.5 mg/kg/day to serovar Typhimurium-infected mice reduced hepatic and splenic bacterial burdens and significantly prolonged survival. These findings show that AR-12 represents a proof of principle that the survival of intracellular bacteria can be suppressed by small-molecule agents that target both innate immunity and host cell factors modulated by bacteria.

scholarly journals Amycomicin: a potent and specific antibiotic discovered with a targeted interaction screen

2018 ◽  
Author(s):  
Gleb Pishchany ◽  
Emily Mevers ◽  
Sula Ndousse-Fetter ◽  
Dennis J. Horvath ◽  
Camila R. Paludo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Fatty Acid ◽  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Fatty Acid Biosynthesis ◽  
Specific Inhibitor ◽  
Mouse Skin ◽  
Acid Biosynthesis ◽  
Microbial Species ◽  
Rdna Sequencing

AbstractThe rapid emergence of antibiotic-resistant pathogenic bacteria has accelerated the search for new antibiotics. Many clinically used antibacterials were discovered through culturing a single microbial species under nutrient-rich conditions, but in the environment, bacteria constantly encounter poor nutrient conditions and interact with neighboring microbial species. In an effort to recapitulate this environment we generated a nine-strain Actinomycete community and used 16S rDNA sequencing to deconvolute the stochastic production of antimicrobial activity that was not observed from any of the axenic cultures. We subsequently simplified the community to just two strains and identified Amycolatopsis sp. AA4 as the producing strain and Streptomyces coelicolor M145 as an inducing strain. Bioassay-guided isolation identified amycomicin, a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Staphylococcus aureus. Amycomicin targets an essential enzyme in fatty acid biosynthesis (FabH) and reduces S. aureus infection in a mouse skin infection model. The discovery of amycomicin demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.SignificanceBacteria, especially actinomycetes, produce the majority of our clinically useful small-molecule antibiotics. Genomic analyses of antibiotic-producing strains indicate that earlier discovery efforts found only a fraction of the likely antibiotic candidates. In an effort to uncover these previously missed candidates we developed an approach that utilizes the ability of microbial communities to produce antibiotics that are not produced by any single member in isolation. Successful communities were established and deconvoluted to identify both producers and inducers of antibiotic activity. One inducer-producer pair made amycomicin, a potent and specific antibiotic against Staphylococcus aureus, an important human pathogen. Amycomicin targets fatty acid biosynthesis and exhibits in vivo efficacy against skin infections in a mouse model.

scholarly journals Suppression of Staphylococcus aureus virulence by a small-molecule compound

2018 ◽  
Vol 115 (31) ◽  
pp. 8003-8008 ◽  
Author(s):  
Peng Gao ◽  
Pak Leung Ho ◽  
Bingpeng Yan ◽  
Kong Hung Sze ◽  
Julian Davies ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Virulence Gene ◽  
Dependent Manner ◽  
Chemical Library ◽  
Virulence Gene Expression ◽  
Small Molecule Compound ◽  
Mouse Model Of Infection

Emerging antibiotic resistance among bacterial pathogens has necessitated the development of alternative approaches to combat drug-resistance-associated infection. The abolition of Staphylococcus aureus virulence by targeting multiple-virulence gene products represents a promising strategy for exploration. A multiplex promoter reporter platform using gfp-luxABCDE dual-reporter plasmids with selected promoters from S. aureus-virulence-associated genes was used to identify compounds that modulate the expression of virulence factors. One small-molecule compound, M21, was identified from a chemical library to reverse virulent S. aureus into its nonvirulent state. M21 is a noncompetitive inhibitor of ClpP and alters α-toxin expression in a ClpP-dependent manner. A mouse model of infection indicated that M21 could attenuate S. aureus virulence. This nonantibiotic compound has been shown to suppress the expression of multiple unrelated virulence factors in S. aureus, suggesting that targeting a master regulator of virulence is an effective way to control virulence. Our results illustrate the power of chemical genetics in the modulation of virulence gene expression in pathogenic bacteria.

scholarly journals Natural Product Inhibition and Enzyme Kinetics Related to Phylogenetic Characterization for Bacterial Peptidyl-tRNA Hydrolase 1

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2281
Author(s):  
D. Scott Strange ◽  
Steven S. Gaffin ◽  
W. Blake Holloway ◽  
Meredyth D. Kinsella ◽  
Jacob N. Wisotsky ◽  
...  
Keyword(s):  
Enzyme Kinetics ◽  
Natural Product ◽  
Small Molecule ◽  
Broad Spectrum ◽  
Pathogenic Bacteria ◽  
Product Inhibition ◽  
Antibiotic Development ◽  
Small Molecule Inhibition ◽  
Loop Region

With the relentless development of drug resistance and re-emergence of many pathogenic bacteria, the need for new antibiotics and new antibiotic targets is urgent and growing. Bacterial peptidyl-tRNA hydrolase, Pth1, is emerging as a promising new target for antibiotic development. From the conserved core and high degree of structural similarity, broad-spectrum inhibition is postulated. However, Pth1 small-molecule inhibition is still in the earliest stages. Focusing on pathogenic bacteria, herein we report the phylogenetic classification of Pth1 and natural product inhibition spanning phylogenetic space. While broad-spectrum inhibition is found, narrow-spectrum and even potentially clade-specific inhibition is more frequently observed. Additionally reported are enzyme kinetics and general in vitro Pth1 solubility that follow phylogenetic boundaries along with identification of key residues in the gate loop region that appear to govern both. The studies presented here demonstrate the sizeable potential for small-molecule inhibition of Pth1, improve understanding of Pth enzymes, and advance Pth1 as a much-needed novel antibiotic target.

scholarly journals Antibiofilm Activity of Small-Molecule ZY-214-4 Against Staphylococcus aureus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingyi Yu ◽  
Lulin Rao ◽  
Lingling Zhan ◽  
Yan Zhou ◽  
Yinjuan Guo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Small Molecule ◽  
Biofilm Formation ◽  
Laser Scanning ◽  
Pathogenic Bacteria ◽  
Cell Aggregation ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Antibiofilm Activity ◽  
Subinhibitory Concentration

Staphylococcus aureus is the most important pathogenic bacteria in humans. As the resistance of S. aureus to existing antibiotics is increasing, there is an urgent need for new anti-infective drugs. S. aureus biofilms cause persistent infections and resist complete eradication with antibiotic therapy. The present study investigated the inhibitory effect of the novel small-molecule ZY-214-4 (C19H11BrNO4) on S. aureus biofilm formation. At a subinhibitory concentration (4 μg/ml), ZY-214-4 had no effect on the growth of S. aureus strains and also showed no cytotoxicity in human normal bronchial epithelial cells (Bease-2B). The results of a semi-quantitative biofilm test showed that ZY-214-4 prevented S. aureus biofilm formation, which was confirmed by scanning electron microscopy and confocal laser scanning microscopy. ZY-214-4 significantly suppressed the production of polysaccharide intercellular adhesion and prevented cell aggregation, and also inhibited the mRNA expression of icaA and other biofilm-related genes (eno, clfA/B, fnbB, fib, ebpS, psmα, and psmβ) in clinical S. aureus isolates. Thus, at a subinhibitory concentration, ZY-214-4 inhibits biofilm formation by preventing cell aggregation, highlighting its clinical potential for preventing or treating S. aureus infections.

scholarly journals Mitigating the Impact of Antibacterial Drug Resistance through Host-Directed Therapies: Current Progress, Outlook, and Challenges

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Chih-Yuan Chiang ◽  
Ijeoma Uzoma ◽  
Richard T. Moore ◽  
Merle Gilbert ◽  
Allen J. Duplantier ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Antibacterial Drug ◽  
Pathogen Virulence ◽  
Fda Approval ◽  
Antibacterial Drug Resistance ◽  
The Impact

ABSTRACT Increasing incidences of multidrug resistance in pathogenic bacteria threaten our ability to treat and manage bacterial infection. The development and FDA approval of novel antibiotics have slowed over the past decade; therefore, the adoption and improvement of alternative therapeutic strategies are critical for addressing the threat posed by multidrug-resistant bacteria. Host-directed therapies utilize small-molecule drugs and proteins to alter the host response to pathogen infection. Here, we highlight strategies for modulating the host inflammatory response to enhance bacterial clearance, small-molecule potentiation of innate immunity, and targeting of host factors that are exploited by pathogen virulence factors. Application of state-of-the-art “omic” technologies, including proteomics, transcriptomics, and image-omics (image-based high-throughput phenotypic screening), combined with powerful bioinformatics tools will enable the modeling of key signaling pathways in the host-pathogen interplay and aid in the identification of host proteins for therapeutic targeting and the discovery of host-directed small molecules that will regulate bacterial infection. We conclude with an outlook on research needed to overcome the challenges associated with transitioning host-directed therapies into a clinical setting.

scholarly journals The glmS ribozyme: use of a small molecule coenzyme by a gene-regulatory RNA

2010 ◽  
Vol 43 (4) ◽  
pp. 423-447 ◽  
Author(s):  
Adrian R. Ferré-D'Amaré
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Active Site ◽  
Messenger Rna ◽  
Pathogenic Bacteria ◽  
Experimental System ◽  
Gram Positive Bacteria ◽  
New Antibiotics ◽  
Glms Ribozyme ◽  
Essential Enzyme

AbstractThe glmS ribozyme is the first known example of a natural ribozyme that has evolved to require binding of an exogenous small molecule for activity. In Gram-positive bacteria, this RNA domain is part of the messenger RNA (mRNA) encoding the essential enzyme that synthesizes glucosamine-6-phosphate (GlcN6P). When present at physiologic concentration, this small molecule binds to the glmS ribozyme and uncovers a latent self-cleavage activity that ultimately leads to degradation of the mRNA. Biochemical and structural studies reveal that the RNA adopts a rigid fold stabilized by three pseudoknots and the packing of a peripheral domain against the ribozyme core. GlcN6P binding to this pre-organized RNA does not induce conformational changes; rather, the small molecule functions as a coenzyme, providing a catalytically essential amine group to the active site. The ribozyme is not a passive player, however. Active site functional groups are essential for catalysis, even in the presence of GlcN6P. In addition to being a superb experimental system with which to analyze how RNA catalysts can exploit small molecule coenzymes to broaden their chemical versatility, the presence of the glmS ribozyme in numerous pathogenic bacteria make this RNA an attractive target for the development of new antibiotics and antibacterial strategies.

scholarly journals Novel Small-molecule Antibacterials against Gram-positive Pathogens of Staphylococcus and Enterococcus Species

Antibiotics ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 210 ◽  
Author(s):  
Marius Seethaler ◽  
Tobias Hertlein ◽  
Björn Wecklein ◽  
Alba Ymeraj ◽  
Knut Ohlsen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pathogenic Bacteria ◽  
In Vivo Studies ◽  
Enterococcus Species ◽  
Gram Positive ◽  
One Pot ◽  
Gram Positive Bacteria ◽  
Hybrid Molecules

Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials.

A privileged ternary blend enabling non-fullerene organic photovoltaics with over 14% efficiency

2020 ◽  
Vol 8 (43) ◽  
pp. 15135-15141
Author(s):  
Jing Yan ◽  
Yuan-Qiu-Qiang Yi ◽  
Jianqi Zhang ◽  
Huanran Feng ◽  
Yanfeng Ma ◽  
...  
Keyword(s):  
Small Molecule ◽  
Organic Photovoltaics ◽  
Power Conversion ◽  
Ternary Blend ◽  
Conversion Efficiencies

Two non-fullerene small molecule acceptors, NT-4F and NT-4Cl, were designed and synthesized. Power conversion efficiencies of 11.44% and 14.55% were achieved for NT-4Cl-based binary and ternary devices, respectively.

Probiotic Displaces Pathogenic Bacteria

2006 ◽  
Vol 37 (7) ◽  
pp. 48
Author(s):  
ERIK GOLDMAN
Keyword(s):  
Pathogenic Bacteria
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