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Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
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Emerging peptide antibiotics with therapeutic potential.

Gregory Upert1, Anatol Luther2, Daniel Obrecht1

  • 1Polyphor Ltd, Hegenheimermattweg 125, 4123 Allschwil, Switzerland.

Medicine in Drug Discovery
|January 5, 2021
PubMed
Summary

This review highlights recent advancements in peptide antibiotics, focusing on novel mechanisms and proven effectiveness in animal models. It explores various peptide types and their targets within bacterial cell membranes.

Keywords:
ADMET, absorption, distribution, metabolism and excretion – toxicity in pharmacokineticsAMP, antimicrobial peptideAMR, antimicrobial resistanceATCC, ATCC cell collectionAntibioticBAM, β-barrel assembly machineryCC50, cytotoxic concentration to kill 50% of cellsCD, circular dichroismCFU, colony forming unitCLSI, clinical and laboratory standards instituteCMS, colistin methane sulfonateDMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholineESKAPE, acronym encompassing six bacterial pathogens (often carrying antibiotic resistance): Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter sppFDA, U. S. Food and Drug AdministrationHABP, hospital acquired bacterial pneumoniaHDP, host-defense peptideHEK293, human embryonic kidney 293 cellsHK-2, human kidney 2 cells (proximal tubular cell line)HepG2, human hepatocellular carcinoma cell lineHpg, 4-hydroxy-phenyl glycineITC, isothermal titration calorimetryKPC, Klebsiella pneumoniae metallo-β-lactamase C resistantLPS, lipopolysaccharideLptA, lipopolysaccharide transport protein ALptC, lipopolysaccharide transport protein CLptD, lipopolysaccharide transport protein DMDR, multidrug-resistantMH-I, Müller-Hinton broth IMH-II, Müller-Hinton broth II (cation adjusted)MIC, minimal inhibitory concentrationMRSA, methicilline-resistant S. aureusMSSA, methicilline-sensitive S. aureusMoA, mechanism (mode) of actionNDM-1, New Delhi metallo-β-lactamase resistantNOAEL, no adverse effect levelODL, odilorhabdinOMPTA (outer membrane targeting antibiotic)OMPTA, outer membrane targeting antibioticOmp, outer membrane proteinPBMC, peripheral mononuclear blood cellPBP, penicillin-binding proteinPBS, phosphate-buffered salinePK, pharmacokineticsPOPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholinePOPG, 2-oleoyl-1-palmitoyl-sn-glycero-3-phospho-(1-glycerol)PrAMPs, polyproline antimicrobial peptidesRBC, red blood cellSAR, structure-activity relationshipSPR, surface plasmon resonanceSPase I, signal peptidase IVABP, ventilator associated bacterial pneumoniaVIM-1, beta-lactamase 2 (K. pneumoniae)VISA, vancomycin-intermediate S. aureusVRE, vancomycin-resistant enterococcusWHO, World Health OrganizationWT, wild typeWTA, wall teichoic acidXDR, extremely drug-resistantantimicrobial peptideantimicrobial resistancebid, bis in die (two times a day)i.p., intraperitoneali.v., intravenouslipopeptidemITT population, minimal intend-to-treat populationpeptide antibiotics.c., subcutaneous

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Area of Science:

  • Microbiology
  • Pharmacology
  • Biochemistry

Background:

  • The rise of antibiotic resistance necessitates the development of novel antimicrobial agents.
  • Peptide antibiotics represent a promising class of therapeutics with diverse mechanisms of action.

Purpose of the Study:

  • To review recent progress in peptide antibiotic research.
  • To focus on compounds with novel or established modes of action and demonstrated efficacy in animal infection models.
  • To discuss various types of peptide antibiotics and their bacterial targets.

Main Methods:

  • Literature review of recent scientific publications.
  • Analysis of studies on novel drug discovery approaches for peptide antibiotics.
  • Examination of research on linear and macrocyclic peptide antibiotics, and lipopeptides (e.g., polymyxins).

Main Results:

  • Identification of peptide antibiotics with novel or established mechanisms of action.
  • Demonstrated efficacy of selected peptide antibiotics in preclinical animal infection models.
  • Discussion of peptides targeting bacterial plasma and outer membranes.

Conclusions:

  • Peptide antibiotics are a vital area of research for combating bacterial infections.
  • Novel approaches and diverse peptide structures show promise for future drug development.
  • Targeting bacterial membranes is a key strategy for effective peptide antibiotic design.