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1.
Appl Microbiol Biotechnol ; 108(1): 260, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38472422

RESUMO

Staphylococcus aureus is associated with dairy mastitis, which causes serious economic losses to dairy farming industry. Antibacterial peptide NZX showed good antibacterial activity against S. aureus. This study aimed to evaluate pharmacokinetics and pharmacodynamics of NZX against S. aureus-induced mouse mastitis. NZX exhibited potent in vitro antibacterial activity against the test S. aureus strains (minimal inhibitory concentration (MIC): 0.23-0.46 µM), low mutant prevention concentration (MPC: 1.18-3.68 µM), and a long post antibiotic effect (PAE: 2.20-8.84 h), which was superior to those of lincomycin and ceftiofur. Antibacterial mechanisms showed that NZX could penetrate the cell membrane, resulting in obvious cell membrane perforation and morphological changes, and bind to intracellular DNA. Furthermore, NZX had a good stability in milk environment (retention rate: 85.36%, 24 h) than that in mammary homogenate (47.90%, 24 h). In mouse mastitis model, NZX (25-400 µg/gland) could significantly reduce the bacterial load of mammary tissue in a dose-dependent manner. In addition, NZX (100 µg/gland) could relieve the inflammatory symptoms of mammary tissue, and significantly decreased its pathological scores. The concentration-time curve of NZX (100 µg/gland) in the mammary tissue was plotted and the corresponding pharmacokinetic parameters were obtained by non-compartment model calculation. Those parameters of Tmax, T1/2, Cmax and AUC were 0.5 h, 35.11 h, 32.49 µg/g and 391 µg·h/g, respectively. Therefore, these results suggest that NZX could act as a promising candidate for treating dairy mastitis disease caused by S. aureus. KEY POINTS: • NZX could kill S. aureus by dual mechanism involved in membrane and DNA disruption • NZX could relieve S. aureus-induced mouse mastitis • Pharmacokinetic parameters of NZX in mouse mammary gland were obtained.


Assuntos
Mastite Bovina , Infecções Estafilocócicas , Feminino , Camundongos , Animais , Bovinos , Humanos , Staphylococcus aureus , Antibacterianos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Modelos Animais de Doenças , Peptídeos Catiônicos Antimicrobianos/farmacologia , Mastite Bovina/microbiologia , DNA/metabolismo
2.
Molecules ; 29(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474693

RESUMO

Antimicrobial peptides (AMPs), acknowledged as host defense peptides, constitute a category of predominant cationic peptides prevalent in diverse life forms. This study explored the antibacterial activity of α-conotoxin RgIA, and to enhance its stability and efficacy, D-amino acid substitution was employed, resulting in the synthesis of nine RgIA mutant analogs. Results revealed that several modified RgIA mutants displayed inhibitory efficacy against various pathogenic bacteria and fungi, including Candida tropicalis and Escherichia coli. Mechanistic investigations elucidated that these polypeptides achieved antibacterial effects through the disruption of bacterial cell membranes. The study further assessed the designed peptides' hemolytic activity, cytotoxicity, and safety. Mutants with antibacterial activity exhibited lower hemolytic activity and cytotoxicity, with Pep 8 demonstrating favorable safety in mice. RgIA mutants incorporating D-amino acids exhibited notable stability and adaptability, sustaining antibacterial properties across diverse environmental conditions. This research underscores the potential of the peptide to advance innovative oral antibiotics, offering a novel approach to address bacterial infections.


Assuntos
Anti-Infecciosos , Conotoxinas , Camundongos , Animais , Lisina/farmacologia , Leucina/farmacologia , Substituição de Aminoácidos , Conotoxinas/química , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias , Testes de Sensibilidade Microbiana
3.
Bioorg Chem ; 145: 107239, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428282

RESUMO

Antimicrobial resistance (AMR) is a serious global concern and a huge burden on the healthcare system. Antimicrobial peptides (AMPs) are considered as a solution of AMR due to their membrane-lytic and intracellular mode of action and therefore resistance development against AMPs is less frequent. One such AMPs, temporin-L (TL) is a 13-mer peptide reported as a potent and broad-spectrum antibacterial agent with significant immunomodulatory activity. However, TL is toxic to human erythrocytes at their antibacterial concentrations and therefore various analogues were synthesized with potent antimicrobial activity and lower hemolytic activity. In this work, we have selected a non-toxic engineered analogue of TL (eTL) and performed hydrocarbon stapling of amino acid residues at i to i + 4 positions at different part of sequence. The synthesized peptides were investigated against both the gram-positive and gram-negative bacteria as well as methicillin resistant S. aureus, its MIC was measured in the concentrations range of 0.9-15.2 µM. All analogues were found equal or better antibacterial as compared to parent peptide. Interestingly one analogue eTL [5-9] was found to be non-cytotoxic and stable in presence of the human serum. Mode of action studies revealed membrane depolarizing and disruptive mode of action with live MRSA. Further in vivo studies of antimicrobial against MRSA infection and anti-endotoxin activities in mice model revealed potential activity of the stapled peptide analogue. Overall, this reports on stapled analogue of the AMPs highlights an important strategy for the development of new antibacterial therapeutics against AMR.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Animais , Camundongos , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Peptídeo Hidrolases , Bactérias Gram-Positivas , Bactérias Gram-Negativas , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Anti-Infecciosos/farmacologia , Endopeptidases , Hidrocarbonetos , Testes de Sensibilidade Microbiana
4.
Antonie Van Leeuwenhoek ; 117(1): 55, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38488950

RESUMO

Antimicrobial peptides (AMPs) are promising cationic and amphipathic molecules to fight antibiotic resistance. To search for novel AMPs, we applied a computational strategy to identify peptide sequences within the organisms' proteome, including in-house developed software and artificial intelligence tools. After analyzing 150.450 proteins from eight proteomes of bacteria, plants, a protist, and a nematode, nine peptides were selected and modified to increase their antimicrobial potential. The 18 resulting peptides were validated by bioassays with four pathogenic bacterial species, one yeast species, and two cancer cell-lines. Fourteen of the 18 tested peptides were antimicrobial, with minimum inhibitory concentrations (MICs) values under 10 µM against at least three bacterial species; seven were active against Candida albicans with MICs values under 10 µM; six had a therapeutic index above 20; two peptides were active against A549 cells, and eight were active against MCF-7 cells under 30 µM. This study's most active antimicrobial peptides damage the bacterial cell membrane, including grooves, dents, membrane wrinkling, cell destruction, and leakage of cytoplasmic material. The results confirm that the proposed approach, which uses bioinformatic tools and rational modifications, is highly efficient and allows the discovery, with high accuracy, of potent AMPs encrypted in proteins.


Assuntos
Anti-Infecciosos , Proteoma , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Antimicrobianos , Inteligência Artificial , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Bactérias , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia
5.
Int J Mol Sci ; 25(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474156

RESUMO

Obesity represents a worldwide health challenge, and the condition is accompanied by elevated risk of cardiovascular diseases caused by metabolic dysfunction and proinflammatory adipokines. Among those, the immune-modulatory cathelicidin antimicrobial peptide (human: CAMP; murine: CRAMP) might contribute to the interaction of the innate immune system and metabolism in these settings. We investigated systemic CAMP/CRAMP levels in experimental murine models of atherosclerosis, myocardial infarction and cardiovascular patients. Atherosclerosis was induced in low-density lipoprotein receptor-deficient (Ldlr-/-) mice by high-fat diet (HFD). C57BL/6J wild-type mice were subjected to myocardial infarction by permanent or transient left anterior descending (LAD)-ligation. Cramp gene expression in murine organs and tissues was investigated via real-time PCR. Blood samples of 234 adult individuals with or without coronary artery disease (CAD) were collected. Human and murine CAMP/CRAMP serum levels were quantified by ELISA. Atherosclerotic mice exhibited significantly increased CRAMP serum levels and induced Cramp gene expression in the spleen and liver, whereas experimental myocardial infarction substantially decreased CRAMP serum levels. Human CAMP serum quantities were not significantly affected by CAD while being correlated with leukocytes and pro-inflammatory cytokines. Our data show an influence of cathelicidin in experimental atherosclerosis, myocardial infarction, as well as in patients with CAD. Further studies are needed to elucidate the pathophysiological mechanism.


Assuntos
Aterosclerose , Doença da Artéria Coronariana , Infarto do Miocárdio , Adulto , Animais , Humanos , Camundongos , Peptídeos Catiônicos Antimicrobianos/metabolismo , Catelicidinas , Camundongos Endogâmicos C57BL , Camundongos Knockout
6.
Eur J Med Chem ; 268: 116276, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38452726

RESUMO

The emergence of bacterial resistance has posed a significant challenge to clinical antimicrobial treatment, rendering commonly used antibiotics ineffective. The development of novel antimicrobial agents and strategies is imperative for the treatment of resistant bacterial infections. Antimicrobial peptides (AMPs) are considered a promising class of antimicrobial agents due to their low propensity for resistance and broad-spectrum activity. Anoplin is a small linear α-helical natural antimicrobial peptide that was isolated from the venom of the solitary wasp Anplius samariensis. It exhibits rich biological activity, particularly broad-spectrum antimicrobial activity and low hemolytic activity. Over the past three decades, more than 40 research publications on anoplin have been made available online. This review focuses on the advancements of anoplin in antimicrobial research, encompassing its sources, characterization, antimicrobial activity, influencing factors and structural modifications. The aim is to provide assistances for the development of new antimicrobial agents that can combat bacterial resistance.


Assuntos
Anti-Infecciosos , Infecções Bacterianas , Humanos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Anti-Infecciosos/química , Venenos de Vespas/química , Antibacterianos/farmacologia , Bactérias , Testes de Sensibilidade Microbiana
7.
Vet Res ; 55(1): 35, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38520031

RESUMO

The increase in the emergence of antimicrobial resistance has led to great challenges in controlling porcine extraintestinal pathogenic Escherichia coli (ExPEC) infections. Combinations of antimicrobial peptides (AMPs) and antibiotics can synergistically improve antimicrobial efficacy and reduce bacterial resistance. In this study, we investigated the antibacterial activity of porcine myeloid antimicrobial peptide 36 (PMAP-36) in combination with tetracycline against porcine ExPEC PCN033 both in vitro and in vivo. The minimum bactericidal concentrations (MBCs) of AMPs (PMAP-36 and PR-39) against the ExPEC strains PCN033 and RS218 were 10 µM and 5 µM, respectively. Results of the checkerboard assay and the time-kill assay showed that PMAP-36 and antibiotics (tetracycline and gentamicin) had synergistic bactericidal effects against PCN033. PMAP-36 and tetracycline in combination led to PCN033 cell wall shrinkage, as was shown by scanning electron microscopy. Furthermore, PMAP-36 delayed the emergence of PCN033 resistance to tetracycline by inhibiting the expression of the tetracycline resistance gene tetB. In a mouse model of systemic infection of PCN033, treatment with PMAP-36 combined with tetracycline significantly increased the survival rate, reduced the bacterial load and dampened the inflammatory response in mice. In addition, detection of immune cells in the peritoneal lavage fluid using flow cytometry revealed that the combination of PMAP-36 and tetracycline promoted the migration of monocytes/macrophages to the infection site. Our results suggest that AMPs in combination with antibiotics may provide more therapeutic options against multidrug-resistant porcine ExPEC.


Assuntos
Anti-Infecciosos , Peptídeos Catiônicos Antimicrobianos , Infecções por Escherichia coli , Escherichia coli Extraintestinal Patogênica , Doenças dos Roedores , Doenças dos Suínos , Animais , Suínos , Camundongos , Escherichia coli Extraintestinal Patogênica/genética , Peptídeos Antimicrobianos , Antibacterianos/farmacologia , Tetraciclinas , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/veterinária , Doenças dos Suínos/tratamento farmacológico
8.
Amino Acids ; 56(1): 12, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38319435

RESUMO

Temporin-SHf is a linear, ultra-short, hydrophobic, α-helix, and phe-rich cationic antimicrobial peptide. The antitumor activities and mechanism of temporin-SHf-induced cancer cell death are unknown. The temporin-SHf was synthesized by solid-phase Fmoc chemistry and antimicrobial and antitumor activities were investigated. Temporin-SHf was microbiocidal, non-hemolytic, and cytotoxic to human cancer cells but not to non-tumorigenic cells. It affected the cancer cells' lysosomal integrity and caused cell membrane damage. The temporin-SHf inhibited A549 cancer cell proliferation and migration. It is anti-angiogenic and causes cancer cell death through apoptosis. The molecular mechanism of action of temporin-SHf confirmed that it kills cancer cells by triggering caspase-dependent apoptosis through an intrinsic mitochondrial pathway. Owing to its short length and broad spectrum of antitumor activity, temporin-SHf is a promising candidate for developing a new class of anticancer drugs.


Assuntos
Anti-Infecciosos , Neoplasias Pulmonares , Humanos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos Catiônicos Antimicrobianos/farmacologia , Apoptose , Anuros
9.
Parasitol Res ; 123(2): 122, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38311672

RESUMO

Protozoal infections cause significant morbidity and mortality in humans and animals. The use of several antiprotozoal drugs is associated with serious adverse effects and resistance development, and drugs that are more effective are urgently needed. Microorganisms, mammalian cells and fluids, insects, and reptiles are sources of antimicrobial peptides (AMPs) that act against pathogenic microorganisms; these AMPs have been widely studied as a promising alternative therapeutic option to conventional antibiotics, aiming to treat infections caused by multidrug-resistant pathogens. One advantage of AMP molecules is their adaptability, as they can be easily fine-tuned for broad-spectrum or targeted activity by changing the amino acid residues in their sequence. Consequently, these variations in structural and physicochemical properties can alter the antimicrobial activities of AMPs and decrease resistance development. This article presents an overview of peptide activities against amebiasis, giardiasis, trichomoniasis, Chagas disease, leishmaniasis, malaria, and toxoplasmosis. AMPs and their analogs demonstrate great potential as therapeutics, with potent and selective activity, when compared with commercially available drugs, and hold the potential to act as new scaffolds for the development of novel anti-protozoal drugs.


Assuntos
Anti-Infecciosos , Animais , Humanos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Antimicrobianos , Antibacterianos/uso terapêutico , Mamíferos
10.
Dev Comp Immunol ; 154: 105144, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38316232

RESUMO

Antimicrobial peptides (AMPs) are an essential part of the vertebrate innate immune system. Piscidins are a family of AMPs specific in fish. In our previous investigation, we identified four paralogous genes of piscidins in the orange-spotted grouper (Epinephelus coicodes), which exhibited distinct activities against bacteria, fungi, and parasitic ciliated protozoa. Piscidins demonstrated their capability to modulate the expression of diverse immune-related genes; however, their precise immunoregulatory functions remain largely unexplored. In this study, we examined the immunomodulatory properties of putative mature peptides derived from four E. coicodes piscidins (ecPis1S, ecPis2S, ecPis3S, and ecPis4S) in head kidney leukocytes (HKLs) or monocytes/macrophages (MO/MΦ)-like cells isolated from E. coicodes. Our data demonstrate that E. coicodes piscidins exhibit immunomodulatory activities supported by multiple lines of evidence. Firstly, all four piscidins displayed chemotactic activities towards HKLs, with the most potent chemotactic activity observed in ecPis2S. Secondly, stimulation with E. coicodes piscidins enhanced respiratory burst and phagocytic activity in MO/MФ-like cells, with ecPis3S showing the highest efficacy in increasing phagocytosis of MO/MΦ-like cells. Thirdly, mRNA expression levels of chemokine receptors, Toll-like receptors, T cell receptors, and proinflammatory cytokines were modulated to varying extents by the four piscidins in E. coicodes HKLs. Overall, our findings indicate that the immunological activities of these four paralogous piscidins from E. coicodes are exhibited in a paralog-specific and concentration-dependent manner, highlighting their distinct and versatile immunomodulatory properties. This study makes a significant contribution to the field of fish AMPs immunology by elucidating the novel mechanisms through which members of the piscidin family exert their immunomodulatory effects. Moreover, it provides valuable insights for further exploration of fish immunomodulating agents.


Assuntos
Bass , Animais , Bass/genética , Bass/metabolismo , Sequência de Aminoácidos , Peptídeos Antimicrobianos , Quimiotaxia , Explosão Respiratória , Peptídeos Catiônicos Antimicrobianos/metabolismo , Alinhamento de Sequência , Proteínas de Peixes/metabolismo , Macrófagos/metabolismo , Fagocitose
11.
Sci Rep ; 14(1): 4805, 2024 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-38413681

RESUMO

A computational study of the peptides Cruzioseptin-4 and Pictuseptin-1, identified in Cruziohyla calcarifer and Boana picturata respectively, has been carried out. The studies on Cruzioseptin-4 show that it is a cationic peptide with a chain of 23 amino acids that possess 52.17% of hydrophobic amino acids and a charge of + 1.2 at pH 7. Similarly, Pictuseptin-1 is a 22 amino acids peptide with a charge of + 3 at pH 7 and 45.45% of hydrophobic amino acids. Furthermore, the predominant secondary structure for both peptides is alpha-helical. The physicochemical properties were predicted using PepCalc and Bio-Synthesis; secondary structures using Jpred4 and PredictProtein; while molecular docking was performed using Autodock Vina. Geometry optimization of the peptides was done using the ONIOM hybrid method with the HF/6-31G basis set implemented in the Gaussian 09 program. Finally, the molecular docking study indicates that the viable mechanism of action for both peptides is through a targeted attack on the cell membrane of pathogens via electrostatic interactions with different membrane components, leading to cell lysis.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Peptídeos Antimicrobianos , Animais , Peptídeos Catiônicos Antimicrobianos/química , Simulação de Acoplamento Molecular , Anuros/metabolismo , Aminoácidos
12.
Int J Nanomedicine ; 19: 1017-1039, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38317847

RESUMO

Traditional chemotherapy is one of the main methods of cancer treatment, which is largely limited by severe side effects and frequent development of multi-drug resistance by cancer cells. Antimicrobial peptides (AMPs) with high efficiency and low toxicity, as one of the most promising new drugs to replace chemoradiotherapy, have become a current research hotspot, attracting the attention of worldwide researchers. AMPs are natural-source small peptides from the innate immune system, and certain AMPs can selectively kill a broad spectrum of cancer cells while exhibiting less damage to normal cells. Although it involves intracellular mechanisms, AMPs exert their anti-cancer effects mainly through membrane destruction effect; thus, AMPs also hold unique advantages in fighting drug-resistant cancer cells. However, the poor stability and hemolytic toxicity of peptides limit their clinical application. Fortunately, functionalized nanoparticles have many possibilities in overcoming the shortcomings of AMPs, which provides a huge prospect for better application of AMPs. In this paper, we briefly introduce the characteristics and different sources of AMPs, review and summarize the mechanisms of action and the research status of AMPs used as an anticancer therapy, and finally focus on the further use of AMPs nano agents in the anti-cancer direction.


Assuntos
Anti-Infecciosos , Neoplasias , Humanos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos , Anti-Infecciosos/farmacologia , Neoplasias/tratamento farmacológico , Antibacterianos/farmacologia
13.
Theranostics ; 14(3): 1181-1194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38323312

RESUMO

Rationale: Antimicrobial peptide LL-37 has been recognized as a favorable alternative to antibiotics due to its broad antibacterial spectrum, low resistance development and diverse biological activities. However, its high manufactory cost, poor proteolytic stability, and unpredictable cytotoxicity seriously hindered its medical translation. Methods: To push the frontiers of its clinical application, all-hydrocarbon stapling strategy was exploited here for the structural modification of KR-12, the core and minimal fragment of LL-37. Results: Based on a library of KR-12 derivatives that designed and synthesized to be stapled at positions of either i, i+4 or i, i+7, structure to activity relationship was investigated. Among them, KR-12(Q5, D9) with the glutamine and aspartic acid residues stapled displayed increased helical content and positive charge. The reinforced α-helical conformation not only protected it from proteolytic hydrolysis but also improved its antibacterial efficacy via effective membrane perturbation and anti-inflammatory efficacy via compact LPS binding. Besides, the increased positive charge endowed it with an enhanced therapeutic index. On infected wound mouse model, it was demonstrated to eliminate bacteria and promote wound closure and regeneration effectively. Conclusion: Overall, the all-hydrocarbon stapling was proven to lay the foundation for the future development of antibacterial agents. KR-12(Q5, D9) could serve as a lead compound for the clinical treatment of bacterial infections.


Assuntos
Antibacterianos , Peptídeos Catiônicos Antimicrobianos , Animais , Camundongos , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/química , Hidrocarbonetos , Bactérias , Anti-Inflamatórios
14.
Physiol Rep ; 12(3): e15945, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38328863

RESUMO

Antimicrobial peptides (AMPs) constitute a complex network of 10-100 amino acid sequence molecules widely distributed in nature. While over 300 AMPs have been described in mammals, cathelicidins and defensins remain the most extensively studied. Some publications have explored the role of AMPs in COVID-19, but these findings are preliminary, and in vivo studies are still lacking. In this study, we report the plasma levels of five AMPs (LL-37, α-defensin 1, α-defensin 3, ß-defensin 1, and ß-defensin 3), using the ELISA technique (MyBioSource, San Diego, CA, United States, kits MBS2601339 (beta-defensin 1), MBS2602513 (beta-defensin 3), MBS703879 (alpha-defensin 1), MBS706289 (alpha-defensin 3), MBS7234921 (LL37)), and the measurement of six cytokines (tumor necrosis factor-α, interleukin-1ß, interleukin-6, interleukin-10, interferon-γ, and monocyte chemoattractant protein-1), through the magnetic bead immunoassay Milliplex® and the MAGPIX® System (MilliporeSigma, Darmstadt, Germany, kit HCYTOMAG-60 K (cytokines)), in 15 healthy volunteers, 36 COVID-19 patients without Acute Kidney Injury (AKI) and 17 COVID-19 patients with AKI. We found increased levels of α-defensin 1, α-defensin 3 and ß-defensin 3, in our COVID-19 population, when compared to healthy controls, along with higher levels of interleukin-6, interleukin-10, interferon-γ, and monocyte chemoattractant protein-1. These findings suggest that these AMPs and cytokines may play a crucial role in the systemic inflammatory response and tissue damage characterizing severe COVID-19. The levels of α-defensin 1 and α-defensin 3 were significantly higher in COVID-19 AKI group in comparison to the non-AKI group. Furthermore, IL-10 and the product IL-10 × IL-1B showed excellent performance in discriminating AKI, with AUCs of 0.86 and 0.88, respectively. Among patients with COVID-19, AMPs may play a key role in the inflammation process and disease progression. Additionally, α-defensin 1 and α-defensin 3 may mediate the AKI process in these patients, representing an opportunity for further research and potential therapeutic alternatives in the future.


Assuntos
Injúria Renal Aguda , COVID-19 , alfa-Defensinas , beta-Defensinas , Animais , Humanos , beta-Defensinas/metabolismo , Interleucina-10 , Peptídeos Catiônicos Antimicrobianos/metabolismo , Quimiocina CCL2 , SARS-CoV-2/metabolismo , Peptídeos Antimicrobianos , Interleucina-6 , Interferon gama , Estado Terminal , Citocinas/metabolismo , Biomarcadores , Injúria Renal Aguda/diagnóstico , Mamíferos/metabolismo
15.
Bioorg Chem ; 145: 107151, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38359706

RESUMO

Antimicrobial peptides (AMPs) are a group of polypeptide chains that have the property to target and kill a myriad of microbial organisms including viruses, bacteria, protists, etc. The first discovered AMP was named gramicidin, an extract of aerobic soil bacteria. Further studies discovered that these peptides are present not only in prokaryotes but in eukaryotes as well. They play a vital role in human innate immunity and wound repair. Consequently, they have maintained a high level of intrigue among scientists in the field of immunology, especially so with the rise of antibiotic-resistant pathogens decreasing the reliability of antibiotics in healthcare. While AMPs have promising potential to substitute for common antibiotics, their use as effective replacements is barred by certain limitations. First, they have the potential to be cytotoxic to human cells. Second, they are unstable in the blood due to action by various proteolytic agents and ions that cause their degradation. This review provides an overview of the mechanism of AMPs, their limitations, and developments in recent years that provide techniques to overcome those limitations. We also discuss the advantages and drawbacks of AMPs as a replacement for antibiotics as compared to other alternatives such as synthetically modified bacteriophages, traditional medicine, and probiotics.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Peptídeos Antimicrobianos , Humanos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Reprodutibilidade dos Testes , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Bactérias
16.
J Med Chem ; 67(5): 4131-4149, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38420875

RESUMO

In the pursuit of combating multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as promising agents; however, their application in clinical settings still presents challenges. Specifically, the exploration of crucial structural parameters that influence the antibacterial spectrum of AMPs and the subsequent development of tailored variants with either broad- or narrow-spectrum characteristics to address diverse clinical therapeutic needs has been overlooked. This study focused on investigating the effects of amino acid sites and hydrophobicity on the peptide's antibacterial spectrum through Ala scanning and fixed-point hydrophobic amino acid substitution techniques. The findings revealed that specific amino acid sites played a pivotal role in determining the antibacterial spectrum of AMPs and confirmed that broadening the spectrum could be achieved only by increasing hydrophobicity at certain positions. In conclusion, this research provided a theoretical basis for future precise regulation of an antimicrobial peptide's spectrum by emphasizing the intricate balance between amino acid sites and hydrophobicity.


Assuntos
Anti-Infecciosos , Peptídeos Catiônicos Antimicrobianos , Peptídeos Catiônicos Antimicrobianos/química , Antibacterianos/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Aminoácidos/farmacologia , Aminoácidos/química , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana
17.
Eur J Med Chem ; 268: 116224, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38387338

RESUMO

The emergence of bacterial strains resistant to antibiotics is a major issue in the medical field. Antimicrobial peptides are widely studied as they do not generate as much resistant bacterial strains as conventional antibiotics and present a broad range of activity. Among them, the homopolypeptide poly(l-arginine) presents promising antibacterial properties, especially in the perspective of its use in biomaterials. Linear poly(l-arginine) has been extensively studied but the impact of its 3D structure remains unknown. In this study, the antibacterial properties of newly synthesized branched poly(l-arginine) peptides, belonging to the family of multiple antigenic peptides, are evaluated. First, in vitro activities of the peptides shows that branched poly(l-arginine) is more efficient than linear poly(l-arginine) containing the same number of arginine residues. Surprisingly, peptides with more arms and more residues are not the most effective. To better understand these unexpected results, interactions between these peptides and the membranes of Gram positive and Gram negative bacteria are simulated thanks to molecular dynamic. It is observed that the bacterial membrane is more distorted by the branched structure than by the linear one and by peptides containing smaller arms. This mechanism of action is in full agreement with in vitro results and suggest that our simulations form a robust model to evaluate peptide efficiency towards pathogenic bacteria.


Assuntos
Antibacterianos , Simulação de Dinâmica Molecular , Peptídeos , Antibacterianos/farmacologia , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Arginina/farmacologia , Bactérias , Testes de Sensibilidade Microbiana
18.
Sci Rep ; 14(1): 4641, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409391

RESUMO

Antimicrobial resistance presents a pressing challenge to public health, which requires the search for novel antimicrobial agents. Various experimental and theoretical methods are employed to understand drug-target interactions and propose multistep solutions. Nonetheless, efficient screening of drug databases requires rapid and precise numerical analysis to validate antimicrobial efficacy. Diptool addresses this need by predicting free energy barriers and local minima for drug translocation across lipid membranes. In the current study employing Diptool free energy predictions, the thermodynamic commonalities between selected antimicrobial molecules were characterized and investigated. To this end, various clustering methods were used to identify promising groups with antimicrobial activity. Furthermore, the molecular fingerprinting and machine learning approach (ML) revealed common structural elements and physicochemical parameters in these clusters, such as long carbon chains, charged ammonium groups, and low dipole moments. This led to the establishment of guidelines for the selection of effective antimicrobial candidates based on partition coefficients (logP) and molecular mass ranges. These guidelines were implemented within the Reinforcement Learning for Structural Evolution (ReLeaSE) framework, generating new chemicals with desired properties. Interestingly, ReLeaSE produced molecules with structural profiles similar to the antimicrobial agents tested, confirming the importance of the identified features. In conclusion, this study demonstrates the ability of molecular fingerprinting and AI-driven methods to identify promising antimicrobial agents with a broad range of properties. These findings deliver substantial implications for the development of antimicrobial drugs and the ongoing battle against antibiotic-resistant bacteria.


Assuntos
Anti-Infecciosos , Peptídeos Catiônicos Antimicrobianos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Antibacterianos/farmacologia , Bactérias , Aprendizado de Máquina
19.
Int J Mol Sci ; 25(4)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38396798

RESUMO

Currently, viable antibiotics available to mitigate infections caused by drug-resistant Gram-negative bacteria are highly limited. Thanatin, a 21-residue-long insect-derived antimicrobial peptide (AMP), is a promising lead molecule for the potential development of novel antibiotics. Thanatin is extremely potent, particularly against the Enterobacter group of Gram-negative pathogens, e.g., E. coli and K. pneumoniae. As a mode of action, cationic thanatin efficiently permeabilizes the LPS-outer membrane and binds to the periplasmic protein LptAm to inhibit outer membrane biogenesis. Here, we have utilized N-terminal truncated 16- and 14-residue peptide fragments of thanatin and investigated structure, activity, and selectivity with correlating modes of action. A designed 16-residue peptide containing D-Lys (dk) named VF16 (V1PIIYCNRRT-dk-KCQRF16) demonstrated killing activity in Gram-negative bacteria. The VF16 peptide did not show any detectable toxicity to the HEK 293T cell line and kidney cell line Hep G2. As a mode of action, VF16 interacted with LPS, permeabilizing the outer membrane and binding to LptAm with high affinity. Atomic-resolution structures of VF16 in complex with LPS revealed cationic and aromatic surfaces involved in outer membrane interactions and permeabilization. Further, analyses of an inactive 14-residue native thanatin peptide (IM14: IIYCNRRTGKCQRM) delineated the requirement of the ß-sheet structure in activity and target interactions. Taken together, this work would pave the way for the designing of short analogs of thanatin-based antimicrobials.


Assuntos
Proteínas de Escherichia coli , Lipopolissacarídeos , Lipopolissacarídeos/metabolismo , Peptídeos Antimicrobianos , Escherichia coli/metabolismo , Peptídeos Catiônicos Antimicrobianos/química , Antibacterianos/química , Bactérias Gram-Negativas/metabolismo , Testes de Sensibilidade Microbiana , Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli/metabolismo
20.
Int J Mol Sci ; 25(4)2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38397022

RESUMO

Piperazic acid is a cyclic nonproteinogenic amino acid that contains a hydrazine N-N bond formed by a piperazate synthase (KtzT-like). This amino acid, found in bioactive natural products synthesized by non-ribosomal peptide synthetases (NRPSs), confers conformational constraint to peptides, an important feature for their biological activities. Genome mining of Streptomyces strains has been revealed as a strategy to identify biosynthetic gene clusters (BGCs) for potentially active compounds. Moreover, the isolation of new strains from underexplored habitats or associated with other organisms has allowed to uncover new BGCs for unknown compounds. The in-house "Carlos Sialer (CS)" strain collection consists of seventy-one Streptomyces strains isolated from the cuticle of leaf-cutting ants of the tribe Attini. Genomes from twelve of these strains have been sequenced and mined using bioinformatics tools, highlighting their potential to encode secondary metabolites. In this work, we have screened in silico those genomes, using KtzT as a hook to identify BGCs encoding piperazic acid-containing compounds. This resulted in uncovering the new BGC dpn in Streptomyces sp. CS113, which encodes the biosynthesis of the hybrid polyketide-depsipeptide diperamycin. Analysis of the diperamycin polyketide synthase (PKS) and NRPS reveals their functional similarity to those from the aurantimycin A biosynthetic pathway. Experimental proof linking the dpn BGC to its encoded compound was achieved by determining the growth conditions for the expression of the cluster and by inactivating the NRPS encoding gene dpnS2 and the piperazate synthase gene dpnZ. The identity of diperamycin was confirmed by High-Resolution Mass Spectrometry (HRMS) and Nuclear Magnetic Resonance (NMR) and by analysis of the domain composition of modules from the DpnP PKS and DpnS NRPS. The identification of the dpn BGC expands the number of BGCs that have been confirmed to encode the relatively scarcely represented BGCs for depsipeptides of the azinothricin family of compounds and will facilitate the generation of new-to-nature analogues by combinatorial biosynthesis.


Assuntos
Depsipeptídeos , Piridazinas , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Família Multigênica , Depsipeptídeos/genética , Depsipeptídeos/metabolismo , Aminoácidos/metabolismo
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