database filtering
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2021 ◽  
Vol 12 ◽  
Author(s):  
Shravani S. Bobde ◽  
Fahad M. Alsaab ◽  
Guangshuan Wang ◽  
Monique L. Van Hoek

Antimicrobial peptides (AMPs) are ubiquitous amongst living organisms and are part of the innate immune system with the ability to kill pathogens directly or indirectly by modulating the immune system. AMPs have potential as a novel therapeutic against bacteria due to their quick-acting mechanism of action that prevents bacteria from developing resistance. Additionally, there is a dire need for therapeutics with activity specifically against Gram-negative bacterial infections that are intrinsically difficult to treat, with or without acquired drug resistance. Development of new antibiotics has slowed in recent years and novel therapeutics (like AMPs) with a focus against Gram-negative bacteria are needed. We designed eight novel AMPs, termed PHNX peptides, using ab initio computational design (database filtering technology combined with the novel positional analysis on APD3 dataset of AMPs with activity against Gram-negative bacteria) and assessed their theoretical function using published machine learning algorithms, and finally, validated their activity in our laboratory. These AMPs were tested to establish their minimum inhibitory concentration (MIC) and half-maximal effective concentration (EC50) under CLSI methodology against antibiotic resistant and antibiotic susceptible Escherichia coli and Staphylococcus aureus. Laboratory-based experimental results were compared to computationally predicted activities for each of the peptides to ascertain the accuracy of the computational tools used. PHNX-1 demonstrated antibacterial activity (under high and low-salt conditions) against antibiotic resistant and susceptible strains of Gram-positive and Gram-negative bacteria and PHNX-4 to -8 demonstrated low-salt antibacterial activity only. The AMPs were then evaluated for cytotoxicity using hemolysis against human red blood cells and demonstrated some hemolysis which needs to be further evaluated. In this study, we successfully developed a design methodology to create synthetic AMPs with a narrow spectrum of activity where the PHNX AMPs demonstrated higher antibacterial activity against Gram-negative bacteria compared to Gram-positive bacteria. Thus, these peptides present novel synthetic peptides with a potential for therapeutic use. Based on our findings, we propose upfront selection of the peptide dataset for analysis, an additional step of positional analysis to add to the ab initio database filtering technology (DFT) method, and we present laboratory data on the novel, synthetically designed AMPs to validate the results of the computational approach. We aim to conduct future in vivo studies which could establish these AMPs for clinical use.



Author(s):  
Sneha Raj ◽  
Umamageswaran Venugopal ◽  
Garima Pant ◽  
Mitra Kalyan ◽  
Jesu Arockiaraj ◽  
...  


2020 ◽  
Vol 13 (10) ◽  
pp. 271
Author(s):  
Biswajit Mishra ◽  
Jayaram Lakshmaiah Narayana ◽  
Tamara Lushnikova ◽  
Yingxia Zhang ◽  
Radha M. Golla ◽  
...  

Antibiotic resistance poses a threat to our society, and 10 million people could die by 2050. To design potent antimicrobials, we made use of the antimicrobial peptide database (APD). Using the database filtering technology, we identified a useful template and converted it into an effective peptide WW291 against methicillin-resistant Staphylococcus aureus (MRSA). Here, we compared the antibacterial activity and cytotoxicity of a family of peptides obtained from sequence permutation of WW291. The resulting eight WW peptides (WW291-WW298) gained different activities against a panel of bacteria. While WW295 inhibited the growth of Escherichia coli, WW298 was highly active against S. aureus USA300 LAC. Consistently with this, WW298 was more effective in permeating or depolarizing the S. aureus membranes, whereas WW295 potently permeated the E. coli membranes. In addition, WW298, but not WW295, inhibited the MRSA attachment and could disrupt its preformed biofilms more effectively than daptomycin. WW298 also protected wax moths Galleria mellonella from MRSA infection causing death. Thus, sequence permutation provides one useful avenue to generating antimicrobial peptides with varying activity spectra. Taken together with amino acid composition modulation, these methods may lead to narrow-spectrum peptides that are more promising to selectively eliminate invading pathogens without damaging commensal microbiota.



2020 ◽  
Vol 2 (3) ◽  
pp. 210-222
Author(s):  
Pawel Drozdowski ◽  
Christian Rathgeb ◽  
Benedikt-Alexander Mokros ◽  
Christoph Busch


2019 ◽  
Vol 12 (2) ◽  
pp. 2129-2144 ◽  
Author(s):  
Peng Tan ◽  
Zhenheng Lai ◽  
Qiao Jian ◽  
Changxuan Shao ◽  
Yongjie Zhu ◽  
...  


2019 ◽  
Vol 7 (6) ◽  
pp. 2394-2409 ◽  
Author(s):  
Shuli Chou ◽  
Jiajun Wang ◽  
Lu Shang ◽  
Muhammad Usman Akhtar ◽  
Zhihua Wang ◽  
...  

A narrow-spectrum antimicrobial peptide was obtained via database-filtering technology and symmetric-structure; the peptide disturbed bacterial membrane and reduced the cytokine levels in serum in the mouse model.



2015 ◽  
Vol 34 (6-7) ◽  
pp. 485-492 ◽  
Author(s):  
Kalev Takkis ◽  
Alfonso T. García-Sosa ◽  
Sulev Sild


2012 ◽  
Vol 134 (30) ◽  
pp. 12426-12429 ◽  
Author(s):  
Biswajit Mishra ◽  
Guangshun Wang
Keyword(s):  




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