Bacterial pathogens-strategies to defeat_8CB0
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Bacterial and viral pathogens
Strategies to defeat the enemyWiesław Swietnicki, Ph.D.
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BackgroundSolutions Problems
Therapeutics-antibioticsBacteria
VaccinesBacteria and
viruses
Antibiotic resistanceSpecificity/side effectsPossibility of genetically-
engineered resistance
Recombinant- time to design, limited antigen repertoire
Live- faster, side effects
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Therapeutic strategiesSolutions Pros/Cons
Metabolic networkBacteria mostly
Virulence systemsBacteria
Conserved – universal target, longer to develop resistance
Takes time to starve bacteria
Independent of antibiotics/vaccines – can defeat genetically-engineered species
Host kills the pathogenCannot reverse effects of
secreted toxic proteins
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VaccinesSolutions Pros/ConsRecombinant
Natural/live
Defined antigen target Intra- and extracellular
pathogensLow costLimited antigen variabilityTime to develop immunity
Broad antigen repertoireLow costVERY effectiveSide effectsTime to develop immunity
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Metabolic networkEasy to build a model and analyzeTargets easily identified and structures
known/models builtSelective for bacteriaStrategy- block active siteRational design – tools developedResistance- after along timeRequires low capital to design drugs –
Poland?
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Potential targetsClass A, B and C Select AgentsRegular pathogensExamples: amino acid biosynthesis, fatty acid
biosynthesis, nutrient procurementDrugs- small molecules
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Examples Bacteria
Small molecules
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Metabolic networksGenome sequenced- 1-2 days nowTargets identified- genome analysis
(MetaCyc)- 1 dayModel constructed -1 dayComputational screen – 1 dayIn vitro testing-1 monthAnalogs search and screen– 1 monthOptimization- cell culture - 3-6 monthsFinal test in a cell culture – 1 monthnM and below- X-ray data for co-crystals – 1
year
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Virulence systems-rationalGenome sequenced- 1-2 daysTargets identified- systems biology analysis - 1
dayModel constructed -1 dayComputational screen – 1 dayIn vitro testing-1 monthAnalogs search and screen– 1 monthOptimization- cell culture - 3-6 monthsFinal test in a cell culture – 1 monthnM and below- X-ray data for co-crystals – 1 year
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Phenotypic screensHTS assay design 1-3 months2000K screen -1-2 weeks50 selectedAnalogs search and screen– 1 monthOptimization- cell culture - 3-6 monthsFinal test in cell culture – 1 monthnM and below- extensive chemistry/QSAR– 1-
2 yearsOff-targets search – 1 year or more
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CustomersNATOPharma companies – small to medium size
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ExamplesViruses
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Live vaccinesGenome sequencing 2-3 daysTarget identification 1 -3 days Cell entry
Protein processingMetabolismViral assemblyStructural proteins
Genetic engineering 3 monthsReconstruction - synthetic biologyEpitope grafting – safe viruses, bacteria
Animal validation 8 months(6 months protocol + 2 months experiments)
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Recombinant vaccinesTargets validated 8 monthsSingle/multiple proteins tested 8 monthsVLPs
Capsid assembly system testing 3 months
Animal testing 8 months
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Small moleculesCell entry – membrane fusionProtein processing- viral proteasesMetabolism – viral enzymesViral assembly – structural proteins
Each strategy requires - 3+ years to optimize
- an HTS screening system (computational or
experimental)
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CustomersNATOPharma companies – small to medium size