scholarly journals Antimicrobial Peptides and Proteins: From Nature’s Reservoir to the Laboratory and Beyond

2021 ◽  
Vol 9 ◽  
Author(s):  
Tanumoy Sarkar ◽  
Monikha Chetia ◽  
Sunanda Chatterjee
Keyword(s):  
Antimicrobial Peptides ◽  
Targeted Delivery ◽  
Unnatural Amino Acids ◽  
De Novo ◽  
Multidrug Resistant ◽  
Host Cells ◽  
Natural Sources ◽  
Small Proteins ◽  
The Future ◽  
Synthetic Designs

Rapid rise of antimicrobial resistance against conventional antimicrobials, resurgence of multidrug resistant microbes and the slowdown in the development of new classes of antimicrobials, necessitates the urgent development of alternate classes of therapeutic molecules. Antimicrobial peptides (AMPs) are small proteins present in different lifeforms in nature that provide defense against microbial infections. They have been effective components of the host defense system for a very long time. The fact that the development of resistance by the microbes against the AMPs is relatively slower or delayed compared to that against the conventional antibiotics, makes them prospective alternative therapeutics of the future. Several thousands of AMPs have been isolated from various natural sources like microorganisms, plants, insects, crustaceans, animals, humans, etc. to date. However, only a few of them have been translated commercially to the market so far. This is because of some inherent drawbacks of the naturally obtained AMPs like 1) short half-life owing to the susceptibility to protease degradation, 2) inactivity at physiological salt concentrations, 3) cytotoxicity to host cells, 4) lack of appropriate strategies for sustained and targeted delivery of the AMPs. This has led to a surge of interest in the development of synthetic AMPs which would retain or improve the antimicrobial potency along with circumventing the disadvantages of the natural analogs. The development of synthetic AMPs is inspired by natural designs and sequences and strengthened by the fusion with various synthetic elements. Generation of the synthetic designs are based on various strategies like sequence truncation, mutation, cyclization and introduction of unnatural amino acids and synthons. In this review, we have described some of the AMPs isolated from the vast repertoire of natural sources, and subsequently described the various synthetic designs that have been developed based on the templates of natural AMPs or from de novo design to make commercially viable therapeutics of the future. This review entails the journey of the AMPs from their natural sources to the laboratory.

scholarly journals Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 501 ◽  
Author(s):  
Berthony Deslouches ◽  
Ronald C. Montelaro ◽  
Ken L. Urish ◽  
Yuanpu P. Di
Keyword(s):  
Antimicrobial Peptides ◽  
De Novo ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
Health Crisis ◽  
Test Conditions ◽  
Reduced Activity

The increasing rate of antibiotic resistance constitutes a global health crisis. Antimicrobial peptides (AMPs) have the property to selectively kill bacteria regardless of resistance to traditional antibiotics. However, several challenges (e.g., reduced activity in the presence of serum and lack of efficacy in vivo) to clinical development need to be overcome. In the last two decades, we have addressed many of those challenges by engineering cationic AMPs de novo for optimization under test conditions that typically inhibit the activities of natural AMPs, including systemic efficacy. We reviewed some of the most promising data of the last two decades in the context of the advancement of the field of helical AMPs toward clinical development.

scholarly journals Novel Antibiotic-Free Plasmid Selection System Based on Complementation of Host Auxotrophy in the NAD De Novo Synthesis Pathway

2010 ◽  
Vol 76 (7) ◽  
pp. 2295-2303 ◽  
Author(s):  
Wei-Ren Dong ◽  
Li-Xin Xiang ◽  
Jian-Zhong Shao
Keyword(s):  
Resistance Genes ◽  
De Novo ◽  
Antibiotic Resistance Genes ◽  
Multidrug Resistant ◽  
Host Cells ◽  
Selection System ◽  
E Coli ◽  
Horizontal Spread ◽  
First Time ◽  
Rapid Emergence

ABSTRACT The use of antibiotic resistance genes in plasmids causes potential biosafety and clinical hazards, such as the possibility of horizontal spread of resistance genes or the rapid emergence of multidrug-resistant pathogens. This paper introduces a novel auxotrophy complementation system that allowed plasmids and host cells to be effectively selected and maintained without the use of antibiotics. An Escherichia coli strain carrying a defect in NAD de novo biosynthesis was constructed by knocking out the chromosomal quinolinic acid phosphoribosyltransferase (QAPRTase) gene. The resistance gene in the plasmids was replaced by the QAPRTase gene of E. coli or the mouse. As a result, only expression of the QAPRTase gene from plasmids can complement and rescue E. coli host cells in minimal medium. This is the first time that a vertebrate gene has been used to construct a nonantibiotic selection system, and it can be widely applied in DNA vaccine and gene therapy. As the QAPRTase gene is ubiquitous in species ranging from bacteria to mammals, the potential environmental biosafety problems caused by horizontal gene transfer can be eliminated.

Action mechanism of melittin-derived antimicrobial peptides, MDP1 and MDP2, de novo designed against multidrug resistant bacteria

Amino Acids ◽  
2018 ◽  
Vol 50 (9) ◽  
pp. 1231-1243 ◽  
Author(s):  
Reza Akbari ◽  
Mojdeh Hakemi Vala ◽  
Ali Hashemi ◽  
Hossein Aghazadeh ◽  
Jean-Marc Sabatier ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
De Novo ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Action Mechanism ◽  
Multidrug Resistant Bacteria

scholarly journals Antimicrobial Peptides in the Battle against Orthopedic Implant-Related Infections: A Review

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1918
Author(s):  
Bruna Costa ◽  
Guillermo Martínez-de-Tejada ◽  
Paula A. C. Gomes ◽  
M. Cristina L. Martins ◽  
Fabíola Costa
Keyword(s):  
Antimicrobial Peptides ◽  
Targeted Delivery ◽  
Polymer Brushes ◽  
Multidrug Resistant ◽  
Future Research ◽  
Resistant Bacteria ◽  
Infection Prevalence ◽  
Antibiotic Administration ◽  
Orthopedic Implant ◽  
Research Strategies

Prevention of orthopedic implant-related infections is a major medical challenge, particularly due to the involvement of biofilm-encased and multidrug-resistant bacteria. Current therapies, based on antibiotic administration, have proven to be insufficient, and infection prevalence may rise due to the dissemination of antibiotic resistance. Antimicrobial peptides (AMPs) have attracted attention as promising substitutes of conventional antibiotics, owing to their broad-spectrum of activity, high efficacy at very low concentrations, and, importantly, low propensity for inducing resistance. The aim of this review is to offer an updated perspective of the development of AMPs-based preventive strategies for orthopedic and dental implant-related infections. In this regard, two major research strategies are herein addressed, namely (i) AMP-releasing systems from titanium-modified surfaces and from bone cements or beads; and (ii) AMP immobilization strategies used to graft AMPs onto titanium or other model surfaces with potential translation as coatings. In overview, releasing strategies have evolved to guarantee higher loadings, prolonged and targeted delivery periods upon infection. In addition, avant-garde self-assembling strategies or polymer brushes allowed higher immobilized peptide surface densities, overcoming bioavailability issues. Future research efforts should focus on the regulatory demands for pre-clinical and clinical validation towards clinical translation.

scholarly journals Antimicrobial Peptides: Novel Source and Biological Function With a Special Focus on Entomopathogenic Nematode/Bacterium Symbiotic Complex

2021 ◽  
Vol 12 ◽  
Author(s):  
Surajit De Mandal ◽  
Amrita Kumari Panda ◽  
Chandran Murugan ◽  
Xiaoxia Xu ◽  
Nachimuthu Senthil Kumar ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Antimicrobial Agents ◽  
Entomopathogenic Nematode ◽  
Multidrug Resistant ◽  
Antimicrobial Activities ◽  
Special Focus ◽  
The Novel ◽  
Risk Of Death ◽  
Small Proteins ◽  
Therapeutic Peptides

The rapid emergence of multidrug resistant microorganisms has become one of the most critical threats to public health. A decrease in the effectiveness of available antibiotics has led to the failure of infection control, resulting in a high risk of death. Among several alternatives, antimicrobial peptides (AMPs) serve as potential alternatives to antibiotics to resolve the emergence and spread of multidrug-resistant pathogens. These small proteins exhibit potent antimicrobial activity and are also an essential component of the immune system. Although several AMPs have been reported and characterized, studies associated with their potential medical applications are limited. This review highlights the novel sources of AMPs with high antimicrobial activities, including the entomopathogenic nematode/bacterium (EPN/EPB) symbiotic complex. Additionally, the AMPs derived from insects, nematodes, and marine organisms and the design of peptidomimetic antimicrobial agents that can complement the defects of therapeutic peptides have been used as a template.

scholarly journals Genetic code expansion enables visualization of Salmonella type three secretion system components and secreted effectors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Moirangthem Kiran Singh ◽  
Parisa Zangoui ◽  
Yuki Yamanaka ◽  
Linda J Kenney
Keyword(s):  
Genetic Code ◽  
Unnatural Amino Acids ◽  
Click Reaction ◽  
Host Cells ◽  
Secretion Systems ◽  
Cellular Functions ◽  
Small Proteins ◽  
Type Three Secretion System ◽  
Genetic Code Expansion ◽  
Type Three Secretion

Type three secretion systems enable bacterial pathogens to inject effectors into the cytosol of eukaryotic hosts to reprogram cellular functions. It is technically challenging to label effectors and the secretion machinery without disrupting their structure/function. Herein, we present a new approach for labeling and visualization of previously intractable targets. Using genetic code expansion, we site-specifically labeled SsaP, the substrate specificity switch, and SifA, a here-to-fore unlabeled secreted effector. SsaP was secreted at later infection times; SsaP labeling demonstrated the stochasticity of injectisome and effector expression. SifA was labeled after secretion into host cells via fluorescent unnatural amino acids or non-fluorescent labels and a subsequent click reaction. We demonstrate the superiority of imaging after genetic code expansion compared to small molecule tags. It provides an alternative for labeling proteins that do not tolerate N- or C-terminal tags or fluorophores and thus is widely applicable to other secreted effectors and small proteins.

scholarly journals Engineered Cationic Antimicrobial Peptides To Overcome Multidrug Resistance by ESKAPE Pathogens

2014 ◽  
Vol 59 (2) ◽  
pp. 1329-1333 ◽  
Author(s):  
Berthony Deslouches ◽  
Jonathan D. Steckbeck ◽  
Jodi K. Craigo ◽  
Yohei Doi ◽  
Jane L. Burns ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Antimicrobial Peptides ◽  
De Novo ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Resistant Bacteria ◽  
Clinical Settings ◽  
Eskape Pathogens ◽  
Antibiotic Peptides

ABSTRACTMultidrug resistance constitutes a threat to the medical achievements of the last 50 years. In this study, we demonstrated the abilities of twode novoengineered cationic antibiotic peptides (eCAPs), WLBU2 and WR12, to overcome resistance from 142 clinical isolates representing the most common multidrug-resistant (MDR) pathogens and to display a lower propensity to select for resistant bacteriain vitrocompared to that with colistin and LL37. The results warrant an exploration of eCAPs for use in clinical settings.

Design, 22-step synthesis, and evaluation of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

2018 ◽  
Author(s):  
James Leighton ◽  
Linda M. Suen ◽  
Makeda A. Tekle-Smith ◽  
Kevin S. Williamson ◽  
Joshua R. Infantine ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Functional Group ◽  
Human Cancer ◽  
Natural Sources ◽  
Spongistatin 1 ◽  
Human Cancer Cell Lines ◽  
Drug Conjugates ◽  
Attractive Candidate ◽  
Complex Fragment ◽  
Antibody Drug

With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.<br><div><br></div>

Antimicrobial Peptides and their Multiple Effects at Sub-Inhibitory Concentrations

2020 ◽  
Vol 20 (14) ◽  
pp. 1264-1273 ◽  
Author(s):  
Bruno Casciaro ◽  
Floriana Cappiello ◽  
Walter Verrusio ◽  
Mauro Cacciafesta ◽  
Maria Luisa Mangoni
Keyword(s):  
Antimicrobial Peptides ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Lead Compounds ◽  
Bacterial Pathogenicity ◽  
Growth Inhibitory ◽  
Resistant Strains ◽  
Conventional Antibiotics

The frequent occurrence of multidrug-resistant strains to conventional antimicrobials has led to a clear decline in antibiotic therapies. Therefore, new molecules with different mechanisms of action are extremely necessary. Due to their unique properties, antimicrobial peptides (AMPs) represent a valid alternative to conventional antibiotics and many of them have been characterized for their activity and cytotoxicity. However, the effects that these peptides cause at concentrations below the minimum growth inhibitory concentration (MIC) have yet to be fully analyzed along with the underlying molecular mechanism. In this mini-review, the ability of AMPs to synergize with different antibiotic classes or different natural compounds is examined. Furthermore, data on microbial resistance induction are reported to highlight the importance of antibiotic resistance in the fight against infections. Finally, the effects that sub-MIC levels of AMPs can have on the bacterial pathogenicity are summarized while showing how signaling pathways can be valid therapeutic targets for the treatment of infectious diseases. All these aspects support the high potential of AMPs as lead compounds for the development of new drugs with antibacterial and immunomodulatory activities.

scholarly journals Stereotypic neutralizing VH antibodies against SARS-CoV-2 spike protein receptor binding domain in COVID-19 patients and healthy individuals

2021 ◽  
pp. eabd6990
Author(s):  
Sang Il Kim ◽  
Jinsung Noh ◽  
Sujeong Kim ◽  
Younggeun Choi ◽  
Duck Kyun Yoo ◽  
...  
Keyword(s):  
B Cells ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Healthy Individuals

Stereotypic antibody clonotypes exist in healthy individuals and may provide protective immunity against viral infections by neutralization. We observed that 13 out of 17 patients with COVID-19 had stereotypic variable heavy chain (VH) antibody clonotypes directed against the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. These antibody clonotypes were comprised of immunoglobulin heavy variable (IGHV)3-53 or IGHV3-66 and immunoglobulin heavy joining (IGHJ)6 genes. These clonotypes included IgM, IgG3, IgG1, IgA1, IgG2, and IgA2 subtypes and had minimal somatic mutations, which suggested swift class switching after SARS-CoV-2 infection. The different immunoglobulin heavy variable chains were paired with diverse light chains resulting in binding to the RBD of SARS-CoV-2 spike protein. Human antibodies specific for the RBD can neutralize SARS-CoV-2 by inhibiting entry into host cells. We observed that one of these stereotypic neutralizing antibodies could inhibit viral replication in vitro using a clinical isolate of SARS-CoV-2. We also found that these VH clonotypes existed in six out of 10 healthy individuals, with IgM isotypes predominating. These findings suggest that stereotypic clonotypes can develop de novo from naïve B cells and not from memory B cells established from prior exposure to similar viruses. The expeditious and stereotypic expansion of these clonotypes may have occurred in patients infected with SARS-CoV-2 because they were already present.

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