Antimicrobial and Antibiofilm Activity of UP-5, an Ultrashort Antimicrobial Peptide Designed Using Only Arginine and Biphenylalanine

The recent upsurge of multidrug resistant bacteria (MDRB) among global communities has become one of the most serious challenges facing health professionals and the human population worldwide. Cationic ultrashort antimicrobial peptides (USAMPs) are a promising group of molecules that meet the required criteria of novel antimicrobial drug development. UP-5, a novel penta-peptide, displayed significant antimicrobial activities against various standard and clinical isolates of MDRB. UP-5 displayed MICs values within the range of (10–15 M) and (55–65 M) against Gram-positive and Gram-negative bacteria, respectively. Furthermore, UP-5 displayed antibiofilm activity with minimum biofilm eradication concentration (MBEC) value as equal to twofold higher than MIC value. At the same inhibitory concentrations, UP-5 exhibited very low or negligible toxicity toward human erythrocytes and mammalian cells. Combining UP-5 with conventional antibiotics led to a synergistic or additive mode of action that resulted in the reduction of the MIC values for some of the antibiotics by 99.7% along a significant drop in MIC values of the peptide. The stability profile of UP-5 was evaluated in full mouse plasma and serum with results indicating a more stable pattern in plasma. The present study indicates that USAMPs are promising antimicrobial agents that can avoid the negative characteristics of conventional antimicrobial peptides. Additionally, USAMPs exhibit good to moderate activity against MDRB, negligible toxicity, and synergistic outcomes in combination with conventional antimicrobial agents

Ellagic acid: A potent glyoxalase-I inhibitor with a unique scaffold

The glyoxalase system, particularly glyoxalase-I (GLO-I), has been approved as a potential target for cancer treatment. In this study, a set of structurally diverse polyphenolic natural compounds were investigated as potential GLO-I inhibitors. Ellagic acid was found, computationally and experimentally, to be the most potent GLO-I inhibitor among the tested compounds which showed an IC50 of 0.71 mol L–1. Its binding to the GLO-I active site seemed to be mainly driven by ionic interaction via its ionized hydroxyl groups with the central Zn ion and Lys156, along with other numerous hydrogen bonding and hydrophobic interactions. Due to its unique and rigid skeleton, it can be utilized to search for other novel and potent GLO-I inhibitors via computational approaches such as pharmacophore modeling and similarity search methods. Moreover, an inspection of the docked poses of the tested compounds showed that chlorogenic acid and dihydrocaffeic acid could be considered as lead compounds worthy of further optimization

Anti-bacterial activity of inorganic nanomaterials and their antimicrobial peptide conjugates against resistant and non-resistant pathogens

This review details the antimicrobial applications of inorganic nanomaterials of mostly metallic form, and the augmentation of activity by surface conjugation of peptide ligands. The review is subdivided into three main sections, of which the first describes the antimicrobial activity of inorganic nanomaterials against gram-positive, gram-negative and multidrug-resistant bacterial strains. The second section highlights the range of antimicrobial peptides and the drug resistance strategies employed by bacterial species to counter lethality. The final part discusses the role of antimicrobial peptide-decorated inorganic nanomaterials in the fight against bacterial strains that show resistance. General strategies for the preparation of antimicrobial peptides and their conjugation to nanomaterials are discussed, emphasizing the use of elemental and metallic oxide nanomaterials. Importantly, the permeation of antimicrobial peptides through the bacterial membrane is shown to aid the delivery of nanomaterials into bacterial cells. By judicious use of targeting ligands, the nanomaterial becomes able to differentiate between bacterial and mammalian cells and, thus, reduce side effects. Moreover, peptide conjugation to the surface of a nanomaterial will alter surface chemistry in ways that lead to reduction in toxicity and improvements in biocompatibility

Antimicrobial and Antibiofilm Activity of UP-5, an Ultrashort Antimicrobial Peptide Designed Using Only Arginine and Biphenylalanine

The recent upsurge of multidrug resistant bacteria (MDRB) among global communities has become one of the most serious challenges facing health professionals and the human population worldwide. Cationic ultrashort antimicrobial peptides (USAMPs) are a promising group of molecules that meet the required criteria of novel antimicrobial drug development. UP-5, a novel penta-peptide, displayed significant antimicrobial activities against various standard and clinical isolates of MDRB. UP-5 displayed MICs values within the range of (10–15 μM) and (55–65 μM) against Gram-positive and Gram-negative bacteria, respectively. Furthermore, UP-5 displayed antibiofilm activity with minimum biofilm eradication concentration (MBEC) value as equal to twofold higher than MIC value. At the same inhibitory concentrations, UP-5 exhibited very low or negligible toxicity toward human erythrocytes and mammalian cells. Combining UP-5 with conventional antibiotics led to a synergistic or additive mode of action that resulted in the reduction of the MIC values for some of the antibiotics by 99.7% along a significant drop in MIC values of the peptide. The stability profile of UP-5 was evaluated in full mouse plasma and serum with results indicating a more stable pattern in plasma. The present study indicates that USAMPs are promising antimicrobial agents that can avoid the negative characteristics of conventional antimicrobial peptides. Additionally, USAMPs exhibit good to moderate activity against MDRB, negligible toxicity, and synergistic outcomes in combination with conventional antimicrobial agents

TECHNICAL GUIDANCE ON THE PHYSICOCHEMICAL AND FUNCTIONAL COMPARABILITY EXERCISE FOR TRASTUZUMAB BIOSIMILARS

The introduction of monoclonal antibodies (mAbs) into the field of oncology has revolutionized the treatment options available to clinicians for the treatment of several malignancies. Unlike their classical small molecule drug counterparts, mAbs are large complex biological molecules that are generated using recombinant engineering and produced through the use of living systems. The high complexity of these agents, combined with the complexity of their manufacturing process, poses significant challenges for the pharmaceutical industry in producing exact copies of the originator molecules. With several mAbs losing their patency in recent years, several pharmaceutical manufacturers are pursuing the development of mAb copies or what is known as biosimilars as generic copies to the originator mAbs. Developing a mAb biosimilar requires that the manufacturer performs an extensive comparability exercise between the originator mAb and its biosimilar to provide evidence that the biological copy is similar to the originator in regards to physicochemical and functional properties, non-clinical pharmacodynamics and immunogenicity, and finally, clinical trials to ensure the safety and efficacy of the biological molecule. The inability to perform a high-quality similarity exercise could generate inferior biological copies or what is known as intended copies. Trastuzumab is a humanized mAb that was designed to target HER 2 receptors which are highly expressed in a variety of tumors, including 25-30% of invasive breast carcinomas. The aim of this review is to provide technical guidance regarding the physicochemical and functional similarity exercise for pharmaceutical personnel working in the research and development of Trastuzumab biosimilars in addition to regulatory officer’s worldwide reviewing biosimilars dossiers within public health authorities. This data will provide valuable information in detailing the main quality parameters needed to demonstrate the analytical similarity of any Trastuzumab biosimilar to its reference product

Enhanced Antimicrobial Activity of AamAP1-Lysine, a Novel Synthetic Peptide Analog Derived from the Scorpion Venom Peptide AamAP1

There is great interest in the development of antimicrobial peptides as a potentially novel class of antimicrobial agents. Several structural determinants are responsible for the antimicrobial and cytolytic activity of antimicrobial peptides. In our study, a new synthetic peptide analog, AamAP1-Lysine from the naturally occurring scorpion venom antimicrobial peptide AamAP1, was designed by modifying the parent peptide in order to increase the positive charge and optimize other physico-chemical parameters involved in antimicrobial activity. AamAP1-Lysine displayed potent antibacterial activity against Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was in the range of 5 to 15 µM with a 10 fold increase in potency over the parent peptide. The hemolytic and antiproliferative activity of AamAP1-Lysine against eukaryotic mammalian cells was minimal at the concentration range needed to inhibit bacterial growth. The antibacterial mechanism analysis indicated that AamAP1-Lysine is probably inducing bacterial cell death through membrane damage and permeabilization determined by the release of β-galactosidase enzyme from peptide treated E. coli cells. DNA binding studies revealed that AamAP1-Lysine caused complete retardation of DNA migration and could display intracellular activities in addition to the membrane permeabilization mode of action reported earlier. In conclusion, AamAP1-Lysine could prove to be a potential candidate for antimicrobial drug development in future studies

Challenges in Rendering Arabic Text to English Using Machine Translation: A Systematic Literature Review

The Arabic text can be translated into English using a variety of machine translation techniques. The translation of Arabic text into English still poses a number of challenges in contemporary Arabic. To identify these challenges that encounter while translating Arabic text into English using machine translation, a systematic literature review (SLR) approach is used. The SLR steps—protocol creation, first and final selection, quality assessment, data extraction and synthesis—are used. Nineteen challenges are reported during the SLR process based on fifty-six research papers. The four most important problems are carefully examined, and the possible solutions of other researchers are discussed. Word sense disambiguation, Arabic named entity, rich and complex morphology and low resource are the four critical challenges during rendering Arabic text to English text. Other challenges are also reported in this article

In vivo antimicrobial activity of the hybrid peptide H4: a follow-up study

Ammar Almaaytah,1 Qosay Albalas,2 Karem H Alzoubi3 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Background: The consistent upsurge in antimicrobial resistance globally is threatening the world population with the prospect of facing the post-antibiotic era. Dry pipelines and a drastic decrease of antimicrobial drug development accompany this rise in antimicrobial resistance. Governments and health authorities are calling for the development of novel classes of antimicrobial agents that would tackle this problem. Antimicrobial peptides represent a promising group of molecules for antimicrobial drug development due to their potency and rapid mode of killing. However, several obstacles, such as high mammalian cell toxicity and lack of target selectivity, have challenged the development of such agents. Methods: We have recently designed a novel hybrid peptide named H4 that exhibits potent antimicrobial activity and low toxicity in vitro. In order to confirm the potential therapeutic efficacy and safety of the peptide, we evaluated the in vivo activity and toxicity of H4 against Staphylococcus aureus peritonitis mice model. Results: Our results indicate that H4 is highly potent in eradicating bacterial infections in vivo with an effective dose50 value of 4.55±0.89 mg/kg. Additionally, the acute systemic toxicity results indicate that the peptide exhibits a high therapeutic index with no significant negative effects on the function of major body organs. Conclusion: H4 is a novel hybrid peptide with great potential for antimicrobial drug development. Keywords: antimicrobial peptides, hybrid peptides, in vivo activity, hybridization, antimicrobial resistance, drug developmen

The evaluation of the synergistic antimicrobial and antibiofilm activity of AamAP1-Lysine with conventional antibiotics against representative resistant strains of both Gram-positive and Gram-negative bacteria

Ammar Almaaytah,1 Ahmad Abualhaijaa,2 Obadah Alqudah31Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Applied Biological Sciences, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Legal Medicine, Toxicology and Forensic Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, JordanBackground and purpose: Antimicrobial resistance toward antibiotics is reaching historical unprecedented levels. There is an urgent and imminent need to develop novel antimicrobial alternatives. Antimicrobial peptides could prove to be a successful group of antimicrobials for drug development. Recently, we have designed a novel synthetic peptide named AamAP1-Lysine. The peptide displayed potent wide-spectrum antimicrobial activities against Gram-positive and Gram-negative bacteria. The purpose of this study is to evaluate the antimicrobial effect of combining AamAP1-Lysine with five different conventional antibiotics each representing a distinct mechanism of action in order to explore the possibility of producing a synergistic mode of action against a resistant strain of Gram-positive and a resistant strain of Gram-negative bacteria.Methodology: The antimicrobial activity of AamAP1-Lysine in combination with five different antibiotics were evaluated for their antimicrobial activity employing standard antimicrobial assays, the synergistic activity of the peptide-antibiotic combinations were evaluated using checkerboard technique in addition to real-time time-kill assays. For the antibiofilm studies, the MBEC values were determined by employing the Calgary device.Results: The combination strategy displayed potent synergistic activities against planktonic bacteria in a significant number of peptide-antibiotic combinations. The synergistic activity managed to reduce the effective minimum inhibitory concentration (MIC) concentrations dramatically with some combinations exhibiting a 64-fold decrease in the effective MIC of AamAP1-Lysine individually. Additionally, the combined synergistic activities of the peptide antibiotics were evaluated, and our results have identified two peptide antibiotic combinations with potent synergistic activities against biofilm growing strains of resistant bacteria.Conclusion: Our results clearly indicate that peptide-antibiotic combinations could prove to be a very effective strategy in combatting multidrug-resistant bacteria and biofilm caused infections.Keywords: antimicrobial peptides, AamAP1-Lysine, bacterial resistance, antibiofilm, synerg