scholarly journals Beyond antibacterials – exploring bacteriophages as antivirulence agents

2021 ◽  
Vol 68 ◽  
pp. 166-173
Author(s):  
Yang Shen ◽  
Martin J Loessner
Keyword(s):  
Antivirulence Agents

scholarly journals Discovery of uncompetitive inhibitors of SapM that compromise intracellular survival of Mycobacterium tuberculosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paulina Fernández-Soto ◽  
Joshua Casulli ◽  
Danilo Solano-Castro ◽  
Pablo Rodríguez-Fernández ◽  
Thomas A. Jowitt ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Francisella Tularensis ◽  
Virulence Factor ◽  
Chemical Properties ◽  
Full Potential ◽  
Mechanism Of Inhibition ◽  
Physico Chemical ◽  
Microbial Infections ◽  
Mechanism Of Catalysis ◽  
Antivirulence Agents

AbstractSapM is a secreted virulence factor from Mycobacterium tuberculosis critical for pathogen survival and persistence inside the host. Its full potential as a target for tuberculosis treatment has not yet been exploited because of the lack of potent inhibitors available. By screening over 1500 small molecules, we have identified new potent and selective inhibitors of SapM with an uncompetitive mechanism of inhibition. The best inhibitors share a trihydroxy-benzene moiety essential for activity. Importantly, the inhibitors significantly reduce mycobacterial burden in infected human macrophages at 1 µM, and they are selective with respect to other mycobacterial and human phosphatases. The best inhibitor also reduces intracellular burden of Francisella tularensis, which secretes the virulence factor AcpA, a homologue of SapM, with the same mechanism of catalysis and inhibition. Our findings demonstrate that inhibition of SapM with small molecule inhibitors is efficient in reducing intracellular mycobacterial survival in host macrophages and confirm SapM as a potential therapeutic target. These initial compounds have favourable physico-chemical properties and provide a basis for exploration towards the development of new tuberculosis treatments. The efficacy of a SapM inhibitor in reducing Francisella tularensis intracellular burden suggests the potential for developing broad-spectrum antivirulence agents to treat microbial infections.

New Strategies Targeting Virulence Factors of Staphylococcus aureus and Pseudomonas aeruginosa

2017 ◽  
Vol 38 (03) ◽  
pp. 346-358 ◽  
Author(s):  
Bruno François ◽  
Charles-Edouard Luyt ◽  
C. Stover ◽  
Jeffery Brubaker ◽  
Jean Chastre ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Effective Utilization ◽  
Mechanically Ventilated ◽  
Stage Of Development ◽  
Antivirulence Agents ◽  
Interventional Therapies ◽  
Improve Patient ◽  
New Strategies

AbstractMorbidity, mortality, and economic burden of nosocomial pneumonia caused by Staphylococcus aureus and Pseudomonas aeruginosa remain high in mechanically ventilated and hospitalized patients despite the use of empirical antibiotic therapy or antibiotics against specific classes of pathogens and procedures to reduce nosocomial infections in hospital settings. Newer agents that neutralize or inhibit specific S. aureus or P. aeruginosa virulence factors may eliminate or reduce the risk for developing pneumonia before or during mechanical ventilation and may improve patient outcomes through mechanisms that differ from those of antibiotics. In this article, we review the types, mechanisms of action, potential advantages, and stage of development of antivirulence agents (AVAs) that hold promise as alternative preventive or interventional therapies against S. aureus– and P. aeruginosa–associated nosocomial pneumonias. We also present and discuss challenges to the effective utilization of AVAs separately from or in addition to antibiotics and the design of clinical trials and meaningful study end points.

scholarly journals Identification of potential antivirulence agents by substitution-oriented screening for inhibitors of Streptococcus pyogenes sortase A

2019 ◽  
Vol 161 ◽  
pp. 93-100 ◽  
Author(s):  
Magdalena Wójcik ◽  
Nikolaos Eleftheriadis ◽  
Martijn R.H. Zwinderman ◽  
Alexander S.S. Dömling ◽  
Frank J. Dekker ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Sortase A ◽  
Antivirulence Agents

scholarly journals Targeting Quorum Sensing: High-Throughput Screening to Identify Novel LsrK Inhibitors

2019 ◽  
Vol 20 (12) ◽  
pp. 3112 ◽  
Author(s):  
Viviana Gatta ◽  
Polina Ilina ◽  
Alison Porter ◽  
Stuart McElroy ◽  
Päivi Tammela
Keyword(s):  
Quorum Sensing ◽  
High Throughput ◽  
High Throughput Screening ◽  
Enteric Bacteria ◽  
New Class ◽  
Bacterial Pathogenicity ◽  
Autoinducer 2 ◽  
A Cell ◽  
The Moment ◽  
Antivirulence Agents

Since quorum sensing (QS) is linked to the establishment of bacterial infection, its inactivation represents one of the newest strategies to fight bacterial pathogens. LsrK is a kinase playing a key role in the processing of autoinducer-2 (AI-2), a quorum-sensing mediator in gut enteric bacteria. Inhibition of LsrK might thus impair the quorum-sensing cascade and consequently reduce bacterial pathogenicity. Aiming for the development of a target-based assay for the discovery of LsrK inhibitors, we evaluated different assay set-ups based on ATP detection and optimized an automation-compatible method for the high-throughput screening of chemical libraries. The assay was then used to perform the screening of a 2000-compound library, which provided 12 active compounds with an IC50 ≤ 10 µM confirming the effectiveness and sensitivity of our assay. Follow-up studies on the positive hits led to the identification of two compounds, harpagoside and rosolic acid, active in a cell-based AI-2 QS interference assay, which are at the moment the most promising candidates for the development of a new class of antivirulence agents based on LsrK inhibition.

Combinatorial Synthesis and in Vitro Evaluation of a Biaryl Hydroxyketone Library as Antivirulence Agents against MRSA

2014 ◽  
Vol 16 (2) ◽  
pp. 85-91 ◽  
Author(s):  
Guanping Yu ◽  
David Kuo ◽  
Menachem Shoham ◽  
Rajesh Viswanathan
Keyword(s):  
Combinatorial Synthesis ◽  
In Vitro Evaluation ◽  
Antivirulence Agents

scholarly journals Identification and characterization of capsule depolymerase Dpo48 from Acinetobacter baumannii phage IME200

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6173 ◽  
Author(s):  
Yannan Liu ◽  
Zhiqiang Mi ◽  
Liyuan Mi ◽  
Yong Huang ◽  
Puyuan Li ◽  
...  
Keyword(s):  
Amino Acid ◽  
Acinetobacter Baumannii ◽  
Amino Acid Sequences ◽  
Blue Staining ◽  
Tail Fiber ◽  
Host Bacterium ◽  
Drug Resistant ◽  
Extensively Drug Resistant ◽  
Serum Killing ◽  
Antivirulence Agents

Background The emergence of multidrug- or extensively drug-resistant Acinetobacter baumannii has made it difficult to treat and control infections caused by this bacterium. It is urgently necessary to search for alternatives to conventional antibiotics for control of severe A. baumannii infections. In recent years, bacteriophages and their derivatives, such as depolymerases, showed great potential as antibacterial or antivirulence agents against bacterial infections. Nonetheless, unlike broad-spectrum bactericidal antibiotics, phage-encoded depolymerase targets only a limited number of bacterial strains. Therefore, identification of novel depolymerases and evaluation of their ability to control A. baumannii infections is important. Methods A bacteriophage was isolated from hospital sewage using an extensively drug-resistant A. baumannii strain as the host bacterium, and the phage’s plaque morphology and genomic composition were studied. A polysaccharide depolymerase (Dpo48) was expressed and identified, and the effects of pH and temperature on its activity were determined. Besides, a serum killing assay was conducted, and amino acid sequences homologous to those of putative polysaccharide depolymerases were compared. Results Phage IME200 yielded clear plaques surrounded by enlarged halos, with polysaccharide depolymerase activity against the host bacterium. A tail fiber protein with a Pectate_lyase_3 domain was identified as Dpo48 and characterized . Dpo48 was found to degrade the capsule polysaccharide of the bacterial surface, as revealed by Alcian blue staining. Dpo48 manifested stable activity over a broad range of pH (5.0–9.0) and temperatures (20–70 °C). Results from in vitro serum killing assays indicated that 50% serum was sufficient to cause a five log reduction of overnight enzyme-treated bacteria, with serum complement playing an important role in these killing assays. Moreover, Dpo48 had a spectrum of activity exactly the same as its parental phage IME200, which was active against 10 out of 41 A. baumannii strains. Amino acid sequence alignment showed that the putative tail fiber proteins had a relatively short, highly conserved domain in their N-terminal sequences, but their amino acid sequences containing pectate lyase domains, found in the C-terminal regions, were highly diverse. Conclusions Phage-encoded capsule depolymerases may become promising antivirulence agents for preventing and controlling A. baumannii infections.

scholarly journals Structure-Based Discovery of a Novel Small-Molecule Inhibitor of Methicillin-Resistant S. aureus

2019 ◽  
Author(s):  
Jie Liu ◽  
Lina Kozhaya ◽  
Victor J. Torres ◽  
Derya Unutmaz ◽  
Min Lu
Keyword(s):  
Cell Attachment ◽  
Immune Defense ◽  
Methicillin Resistant ◽  
Molecule Inhibitor ◽  
Membrane Perforation ◽  
Host Cell Attachment ◽  
Mrsa Infection ◽  
Mrsa Strains ◽  
Antivirulence Agents

SummaryThe rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains represents a major threat to public health. MRSA elaborates an arsenal of secreted host-damaging virulence factors to mediate pathogenicity and blunt immune defense. Panton-Valentine leukocidin (PVL) and α-toxin are pore-forming cytotoxins of recognized importance in the development of invasive MRSA infection and are thus potential targets for antivirulence therapy. We report the X-ray crystal structures of PVL and α-toxin in their soluble, monomeric and oligomeric, membrane-inserted pore states, in complex with n-tetradecylphosphocholine (C14PC). The structures reveal two evolutionarily conserved phosphatidylcholine binding mechanisms and their roles in modulating host cell attachment, oligomer assembly and membrane perforation. Moreover, we demonstrate that the soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of novel antivirulence agents to combat MRSA.

scholarly journals In-Depth Analysis of the Role of the Acinetobactin Cluster in the Virulence of Acinetobacter baumannii

2021 ◽  
Vol 12 ◽  
Author(s):  
Kelly Conde-Pérez ◽  
Juan C. Vázquez-Ucha ◽  
Laura Álvarez-Fraga ◽  
Lucía Ageitos ◽  
Soraya Rumbo-Feal ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Significant Loss ◽  
Genetic Redundancy ◽  
Double Mutant Strain ◽  
Wide Range ◽  
Depth Analysis ◽  
High Level ◽  
Antivirulence Agents

Acinetobacter baumannii is a multidrug-resistant pathogen that represents a serious threat to global health. A. baumannii possesses a wide range of virulence factors that contribute to the bacterial pathogenicity. Among them, the siderophore acinetobactin is one of the most important, being essential for the development of the infection. In this study we performed an in-depth analysis of the acinetobactin cluster in the strain A. baumannii ATCC 17978. For this purpose, nineteen individual isogenic mutant strains were generated, and further phenotypical analysis were performed. Individual mutants lacking the biosynthetic genes entA, basG, basC, basD, and basB showed a significant loss in virulence, due to the disruption in the acinetobactin production. Similarly, the gene bauA, coding for the acinetobactin receptor, was also found to be crucial for the bacterial pathogenesis. In addition, the analysis of the ΔbasJ/ΔfbsB double mutant strain demonstrated the high level of genetic redundancy between siderophores where the role of specific genes of the acinetobactin cluster can be fulfilled by their fimsbactin redundant genes. Overall, this study highlights the essential role of entA, basG, basC, basD, basB and bauA in the pathogenicity of A. baumannii and provides potential therapeutic targets for the design of new antivirulence agents against this microorganism.

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