A drug candidate for Alzheimer’s and Huntington’s disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides

2021 ◽  
Author(s):  
Freda E -C Jen ◽  
Ibrahim M El-Deeb ◽  
Yaramah M Zalucki ◽  
Jennifer L Edwards ◽  
Mark J Walker ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Peptides ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Proteomic Analysis ◽  
Protein Misfolding ◽  
Membrane Integrity ◽  
Drug Candidate ◽  
Cationic Antimicrobial Peptides ◽  
Broth Microdilution Method

Abstract Background Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat. Objectives To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides. Methods MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2/zinc, LL-37 and/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides. Results Sub-inhibitory concentrations of LL-37 and PBT2/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death. Conclusions Here we show that PBT2, a candidate Alzheimer’s and Huntington’s disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.

scholarly journals Polyamines Can Increase Resistance of Neisseria gonorrhoeae to Mediators of the Innate Human Host Defense

2010 ◽  
Vol 78 (7) ◽  
pp. 3187-3195 ◽  
Author(s):  
Maira Goytia ◽  
William M. Shafer
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Peptides ◽  
Host Defense ◽  
Polymyxin B ◽  
Cellular Functions ◽  
Cationic Antimicrobial Peptides ◽  
Sexually Transmitted ◽  
Bacterial Surface ◽  
Bodily Fluids ◽  
Mucosal Surfaces

ABSTRACT Polyamines are biogenic polycationic molecules involved in key cellular functions. Extracellular polyamines found in bodily fluids or laboratory media can be imported by bacteria or bind to negatively charged bacterial surface structures, where they can impair binding of antimicrobials. We hypothesized that the presence of polyamines in fluids that bathe urogenital mucosal surfaces could alter the susceptibility of the sexually transmitted strict human pathogen Neisseria gonorrhoeae to mediators of the innate host defense. Herein we report that polyamines can significantly increase gonococcal resistance to two structurally diverse cationic antimicrobial peptides (polymyxin B and LL-37) but not to antibiotics that exert activity in the cytosol or periplasm (e.g., ciprofloxacin, spectinomycin, or penicillin). The capacity of polyamines to increase gonococcal resistance to cationic antimicrobial peptides was dose dependent, correlated with the degree of cationicity, independent of a polyamine transport system involving the polyamine permeases PotH and PotI, and was reversible. In addition, we found that polyamines increase gonococcal resistance to complement-mediated killing by normal human serum. We propose that polyamines in genital mucosal fluids may enhance gonococcal survival during infection by reducing bacterial susceptibility to host-derived antimicrobials that function in innate host defense.

Proteomic Analysis of Huntington’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1218-1222
Author(s):  
Shobhit Kumar ◽  
Priyanka Singh ◽  
Shrestha Sharma ◽  
Javed Ali ◽  
Sanjula Baboota ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Proteomic Analysis ◽  
Autosomal Dominant ◽  
Dominant Gene ◽  
Polyglutamine Expansion ◽  
X Ray ◽  
Dna Mutation ◽  
X Ray Crystallography ◽  
Thinking Ability

: Huntington’s disease (HD) is a neurodegenerative disease that is genetically inherited through an autosomal dominant gene located on chromosome 4. HD is caused by DNA mutation (generally 37 or more repetition of CAG nucleotides) that leads to an excessive stretch of glutamine residues. However, the main pathogenesis pathway resulted by polyglutamine expansion in mutant HD is unknown. The characteristics of this disease mostly appear in adults. Patients who suffer from this disease have shown an inability to control physical movements, emotional problems, speech disturbance, dementia, loss of thinking ability and death occurs between 15-20 years from the time of symptomatic onset. This review article suggested that investigation of mutation in the HD gene can be done by proteomic analysis such as mass spectroscopy, gel electrophoresis, western blotting, chromatographic based technology, and X-ray crystallography. The primary aim of proteomics is to focus on the molecular changes occurring in HD, there by enhancing the effectiveness of treatment.

scholarly journals Diphenyl diselenide protects a Caenorhabditis elegans model for Huntington's disease by activation of the antioxidant pathway and a decrease in protein aggregation

Metallomics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1142-1158
Author(s):  
Fabiane Bicca Obetine Baptista ◽  
Leticia Priscilla Arantes ◽  
Marina Lopes Machado ◽  
Aline Franzen da Silva ◽  
Larissa Marafiga Cordeiro ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Misfolding ◽  
Nuclear Translocation ◽  
Oxygen Species ◽  
Diphenyl Diselenide ◽  
Disease Treatment ◽  
C Elegans ◽  
Superoxide Dismutase 3 ◽  
Protein Misfolding And Aggregation

The effect of (PhSe)2 in a C. elegans model for Huntington's disease. Treatment with (PhSe)2 triggered the nuclear translocation and activation of DAF-16 transcription factor in C. elegans, inducing the expression of superoxide dismutase-3 (SOD-3) and heat shock protein-16.2 (HSP-16.2). SOD-3 acts on reactive oxygen species (ROS) detoxification, and HSP-16.2 decreases protein misfolding and aggregation, which occur in HD.

scholarly journals HUNTINGTON’S DISEASE AND EARLYONSET ALZHEIMER’S DISEASE SHARE A TRANSCRIPTOMIC SIGNATURE

2021 ◽  
Author(s):  
Giovanna Carello- Collar ◽  
Marco Antônio De Bastiani ◽  
Eduardo R. Zimmer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Early Onset ◽  
Protein Misfolding ◽  
Functional Enrichment ◽  
Early Onset Dementia ◽  
Transcriptomic Signature ◽  
Transcriptomic Level

Background: Neurodegenerative diseases share progressive loss of neurons and protein misfolding, which ultimately culminates in dementia; many diseases have been identified as causes of early-onset dementia (< 65 years of age) such as Huntington’s disease (HD) and early-onset Alzheimer’s disease (EOAD). Importantly, disease-specific genetic mutations have already been identified for HD and EOAD. Thus, one could suggest that the molecular link between these diseases may arise from alterations at the transcriptomic level, which is yet to be determined. Objective: We aimed at identifying transcriptome similarities between HD and EOAD. Methods: We collected data of the postmortem cerebral cortex from 1 HD and 6 AD microarray studies in the Gene Expression Omnibus. Of note, only subjects with age at death under 65 were selected (HD: n = 158, controls: n = 158; EOAD: n = 65, controls: n = 266). Differential expression and functional enrichment analyses were performed. Results: We identified 1,260 differentially expressed genes and 675 enriched gene ontology terms between HD and EOAD. Conclusion: Our results demonstrate a transcriptomic signature shared by HD and EOAD. Unveiling the similarities between these diseases at the transcriptomic level could advance our knowledge about pathogenesis and may help to develop therapeutic strategies targeting early-onset dementias.

scholarly journals Phase-Variable Expression oflptAModulates the Resistance of Neisseria gonorrhoeae to Cationic Antimicrobial Peptides

2014 ◽  
Vol 58 (7) ◽  
pp. 4230-4233 ◽  
Author(s):  
Justin L. Kandler ◽  
Sandeep J. Joseph ◽  
Jacqueline T. Balthazar ◽  
Vijaya Dhulipala ◽  
Timothy D. Read ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Peptides ◽  
High Frequency ◽  
Lipid A ◽  
Bacterial Resistance ◽  
Phase Variable ◽  
Cationic Antimicrobial Peptides ◽  
Content Type ◽  
Variable Expression

ABSTRACTPhosphoethanolamine (PEA) decoration of lipid A produced byNeisseria gonorrhoeaehas been linked to bacterial resistance to cationic antimicrobial peptides/proteins (CAMPs) andin vivofitness during experimental infection. We now report that thelptAgene, which encodes the PEA transferase responsible for this decoration, is in an operon and that high-frequency mutation in a polynucleotide repeat withinlptAcan influence gonococcal resistance to CAMPs.

scholarly journals Molecular Mechanisms Underlying Muscle Wasting in Huntington’s Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8314
Author(s):  
Manuela Bozzi ◽  
Francesca Sciandra
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Atrophy ◽  
Protein Misfolding ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Protein Quality ◽  
Neurodegenerative Disorder ◽  
Wide Spectrum ◽  
Muscular Tissue

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by pathogenic expansions of the triplet cytosine-adenosine-guanosine (CAG) within the Huntingtin gene. These expansions lead to a prolongation of the poly-glutamine stretch at the N-terminus of Huntingtin causing protein misfolding and aggregation. Huntingtin and its pathological variants are widely expressed, but the central nervous system is mainly affected, as proved by the wide spectrum of neurological symptoms, including behavioral anomalies, cognitive decline and motor disorders. Other hallmarks of HD are loss of body weight and muscle atrophy. This review highlights some key elements that likely provide a major contribution to muscle atrophy, namely, alteration of the transcriptional processes, mitochondrial dysfunction, which is strictly correlated to loss of energy homeostasis, inflammation, apoptosis and defects in the processes responsible for the protein quality control. The improvement of muscular symptoms has proven to slow the disease progression and extend the life span of animal models of HD, underlining the importance of a deep comprehension of the molecular mechanisms driving deterioration of muscular tissue.

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