Multimeric TAT peptides are effective in vitro inhibitors of Staphylococcus saprophyticus

2020 ◽  
Vol 96 (6) ◽  
pp. 1348-1354
Author(s):  
Justin Brian V. Chiongson ◽  
Edna M. Sabido ◽  
Kuo‐Ging Lin ◽  
Glenn V. Alea ◽  
Doralyn S. Dalisay ◽  
...  
Author(s):  
Paul Pagano ◽  
Andrea Marra ◽  
Dean Shinabarger ◽  
Chris Pillar

Abstract Background Omadacycline, an aminomethylcycline, was approved in 2018 for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. In a Phase Ib study, around 34% of the absorbed dose of omadacycline was shown to be excreted in urine—an important property for urinary tract infection (UTI) treatment. Therefore, omadacycline has been studied in two Phase II trials for the treatment of uncomplicated UTIs and acute pyelonephritis. The activity of omadacycline against UTI pathogens in human urine is important to understand in this context. Objectives To study the in vitro activity of omadacycline against UTI pathogens in human urine supplemented with calcium and magnesium. Methods Omadacycline activity was compared with that of levofloxacin against the urinary pathogens Escherichia coli, Klebsiella pneumoniae and Staphylococcus saprophyticus in standard medium, pooled normal human urine and neutral pH-adjusted pooled normal human urine spiked with calcium or magnesium at concentrations consistent with hypercalcaemia and hypermagnesaemia. Results The activities of omadacycline and levofloxacin against these urinary pathogens were lower in urine relative to standard medium; addition of Mg2+ to broth and urine had a further negative impact on omadacycline activity, whereas the addition of Ca2+ had less of an impact. Levofloxacin activity was not substantially reduced in either broth or urine by the addition of divalent cations. Conclusions The activity of omadacycline against UTI organisms was lower in urine relative to standard medium and was negatively impacted by magnesium. Omadacycline displayed slightly reduced activity when excess calcium was present, but, overall, the differences were ≤2-fold. These observations should be considered along with the pharmacokinetics of the agent for clinical context.


2020 ◽  
Vol 13 (2) ◽  
pp. 247-258 ◽  
Author(s):  
A.D. Gong ◽  
G.J. Sun ◽  
Z.Y. Zhao ◽  
Y.C. Liao ◽  
J.B. Zhang

Controlling proliferation and aflatoxin production by Aspergillus flavus is a pressing challenge for global food safety and security. Marine bacterium Staphylococcus saprophyticus strain L-38 showed excellent antifungal activity toward A. flavus in vitro and in vivo. In sealed, non-contact confrontation assays, L-38 completely inhibited conidial germination and mycelial growth of A. flavus through the production of volatile organic compounds (VOCs). Gas chromatography-mass spectrometry identified 3,3-dimethyl-1,2-epoxybutane (3-DE) as the most abundant VOC (32.61% of total peak area, 78% matching). Exposure of A. flavus cultures to synthetic 3-DE similarly demonstrated strong inhibition of growth. Moreover, culture of L-38 in a sealed chamber with maize or peanuts artificially inoculated with A. flavus, at high water activity, resulted in significant inhibition of A. flavus germination and aflatoxin biosynthesis. Scanning electron microscopy of these samples revealed severe damage to conidial cells and hyphae compared to samples not exposed to L-38. L-38 also showed broad and effective antifungal activity toward eight other phytopathogenic fungi including Aspergillus niger, Fusarium verticillioides, Fusarium graminearum, Sclerotinia sclerotiorum, Rhizoctonia solani, Alternaria alternata, Monilinia fructicola, and Botrytis cinerea. This work introduces S. saprophyticus L-38 as a potential biocontrol agent and demonstrates the efficacy of the volatile 3-DE in the control of A. flavus and other destructive plant pathogens for post-harvest food safety.


Author(s):  
Fatemeh Ghasemian ◽  
Shahin Esmaeilnezhad ◽  
MohammadJavad MehdipourMoghaddam

Objective: Bacteriospermia and urogenital infections are common problems in male infertility. This study aimed to evaluate the effects of bacteriospermia on sperm parameters and clinical outcomes in semen samples infected with two common bacteria (Staphylococcus saprophyticus and Escherichia coli) in northern Iran.Methods: Microbiological tests were performed to isolate and identify organisms from 435 semen samples from infertile couples. Semen samples were assessed according to the World Health Organization criteria. The protamine status, chromatin structure, chromatin condensation, and acrosome reaction of sperm and assisted reproductive outcomes were determined in couples with different male infertility factors.Results: Among the total cases, the two most prevalent pathogens were considered: S. saprophyticus (38.2%) and E. coli (52.9%). In the semen samples infected with E. coli, the spontaneous acrosome reaction and abnormal chromatin condensation were more common (p<0.05). Significant increases in abnormal chromatin condensation and deprotamination were seen in the presence of S. saprophyticus. In washed semen, tight adhesion between the sperm midpiece and S. saprophyticus was observed. There was also a significant decrease in the fertilization rate using semen samples infected with S. saprophyticus and E. coli during in vitro fertilization cycles (p<0.001). In addition, the presence of S. saprophyticus and E. coli in semen samples was associated with a lower likelihood of clinical pregnancy in couples with various factors of male infertility.Conclusion: Poor results of assisted reproductive techniques may be correlated with semen samples infected with two common bacteria in northern Iran.


2019 ◽  
Vol 10 ◽  
Author(s):  
Katheryne Benini Martins ◽  
Adriano Martison Ferreira ◽  
Valéria Cataneli Pereira ◽  
Luiza Pinheiro ◽  
Adilson de Oliveira ◽  
...  

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1439 ◽  
Author(s):  
Paweł A. Osmulski ◽  
Przemysław Karpowicz ◽  
Elżbieta Jankowska ◽  
Jonathan Bohmann ◽  
Andrew M. Pickering ◽  
...  

The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 980
Author(s):  
Malick Bio Idrissou ◽  
Alexandre Pichard ◽  
Bryan Tee ◽  
Tibor Kibedi ◽  
Sophie Poty ◽  
...  

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431CEA-luc and SK-OV-31B9 cancer cells that express low and high levels of HER2 receptors, two 111In-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of 111In-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [125I]I-UdR showed that the energy released in the cell nucleus by increasing the RIC’s nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed.


2019 ◽  
Vol 98 (1) ◽  
pp. 373-380 ◽  
Author(s):  
Jinli Wang ◽  
Mingyu Qiao ◽  
Yefeng Zhou ◽  
Hongxu Du ◽  
Jingying Bai ◽  
...  

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