Anti-infectives

 

Discovery and development of new anti-infective agents

Evotec provides bespoke research and development services in the anti-infective disease area that range from target identification to investigational new drug (“IND”). The company has a proven track record of contributing to the identification and characterisation of multiple anti-infective agents from hit identification over pre-clinical candidates through to marketed drugs.

Evotec has established a leading-edge platform enabling the discovery and development of new therapies and therapeutic approaches to treat and prevent serious and life-threatening infections. Integration, innovation and efficiency are the main elements characterising Evotec’s expertise. This also reaches beyond conventional antimicrobial agents into multiple alternative modalities such as targeting virulence attributes, specific pathogen antibodies, combination therapies, antimicrobial peptides (AMPs), and phage technologies.

Our anti-infective discovery team of more than 200 scientists has proven experience on multiple agent classes including small molecules, natural products, biologics, peptides, antibodies, combinations (including beta-lactam / beta-lactamase inhibitors), biocides and vaccines. We carefully evaluate and adopt the most efficient and optimal drug discovery approaches from phenotypic screening to target-based discovery. This maximises the team’s extensive experience in multiple target classes including DNA, RNA, protein, folate, cell wall, and LPS synthesis in addition to characterising compounds with completely novel mechanisms of action (MoA).

Key capabilities of Evotec’s anti-infective discovery platform

EvostrAIn™

  • Comprehensive collection of geographically diverse human pathogenic bacteria and fungi containing reference strains and clinical isolates including the ESKAPE pathogens, strains from the WHO priority pathogen list and CDC antibiotic resistance threats reports
  • Highly characterised and, in many cases, fully sequenced strains with defined mechanisms of resistance used to establish the activity profile of lead compounds and candidates, both in vitro and in vivo
  • Many strains and isolates validated in in vivo models of infection allowing rapid progress and continuity from in vitro to in vivo models of disease

Microbiology & mycology

  • Mechanism of action (MoA) determination and in vitro target validation studies
  • Industry-standard methods adopted, including CLSI and EUCAST, to test compounds for antimicrobial activity against organisms from our extensive collection, EvostrAIn™, or strains provided by our collaborators
  • HTS and medium-throughput screening for hit identification of antimicrobial activity on a BSL 2/ BSL 2+/ BSL 3 contained platform
  • MIC, MBC/MFC, time-kill, PAE and intracellular killing studies using single or combination agents
  • Biofilm formation and eradication assays
  • Frequency of resistance determination and detailed characterisation of resistant mutants
  • Early assessment of cytotoxicity potential against multiple mammalian cell lines
  • Non-clinical in vitro and in vivo PK/PD infection models for the optimisation of drug concentration profiles to maximise bacterial killing and minimise the emergence of resistance, including the hollow fibre infection model (HFIM)
  • Compound/drug combination studies for assessment of synergistic, antagonistic and additive effects
  • Bespoke methods for susceptibility profiling developed for testing novel agents where standardised methods are not appropriate

Virology

  • Continuously expanding portfolio focussing on human respiratory viruses: Respiratory 
  • Syncytial virus (RSV), Human Rhinovirus (HRV), influenza virus, coronavirus
  • Compound testing in cell lines and primary cells
  • Screening assays in 96 and 384-well format; cytotoxicity testing of compounds can be performed in parallel
  • Additional endpoints plaque assays, RT-qPCR
  • Immunology read-out (ELISA, neutralisation assay, immunofluorescence)
  • Selection of resistant virus

Microbial biochemistry

  • Molecular biology including genetic modification of bacteria by CRISPR
  • Target-based assay development for medium and high-throughput screening
  • Surface plasmon resonance (SPR) based assay (Biacore T200)
  • Protein expression and purification
  • Structural biology and X-ray crystallography platforms
  • Enzymology of ß-lactamases, PBPs, bacterial topoisomerases and other relevant targets
  • Label-free bacterial intracellular compound accumulation assay

Target identification and validation

  • Macromolecule synthesis assay (MMS) with wild type (Gram-positive) and wild-type efflux impaired (Gram negatives) reference strains and clinical isolates
  • Whole-genome sequencing (WGS) and functional genomics including RNASeq and TnSeq
  • Bacterial cytological profiling (BCP)
  • Transcriptomics
  • Proteomics
  • Phenotypic Microarrary (Biolog)
  • Cellular target profiling and chemoproteomics
  • Photoaffinity labelling mass spectrometry

In vivo models of infection

  • Evotec specialises in assessing the efficacy of lead and candidate compounds in highly relevant and validated disease models across all important pathogens including ESKAPE organisms, fungi, viruses, and parasites:
    • Gram-positive bacteria (including Staphylococcus aureus, Streptococcus pneumoniae)
    • Gram-negative bacteria (including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumanii)
    • Anaerobes (including Clostridium difficile)
    • Fungal pathogens (including Candida spp., Aspergillus spp., Mucorales, Malassezia spp.)
    • Viruses (including RSV cotton rat and mouse model)
    • Parasites (including Toxoplasma gondii)
  • Extensive range of established models that are well-suited to the development of multiple classes of agent including small molecules, natural products, peptides, antibodies, other biologics and vaccines:
    • Multiple hosts/ rodent species
      • Rat, mouse, guinea pig, hamster, cotton rat, rabbit
    • Immunosuppressed and immunocompetent backgrounds
    • Outbred and inbred mouse strains (transgenic mice available for some models)
    • Multiple sites of infection
      • Lung, thigh, blood (sepsis), skin, urinary tract, GI tract, vagina, bone
    • Multiple routes of administration
      • Intravenous (bolus or prolonged infusion (JVC or femoral) in all species)
      • Subcutaneous (direct injection or SC catheter), iPrecio & Alzet pump 
      • Oral, intraperitoneal, intramuscular, intranasal, intratracheal, pulmonary (nebulised, aerosolised)
    • Full range of endpoints
      • Pathogen burden, survival, pathogen gene expression, toxin production, biomarkers, blood cell analysis, IVIS imaging, qPCR
  • Fully aligned with the principles of NC3Rs (National Committee for the 3Rs (Refinement, Reduction, Replacement)) and ethical alternatives for animal models
    • Galleria mellonella (greater wax moth) larva rapid screening models to pre-assess compound efficacy and tolerability

ADMET & PK/PD profiling

  • Translation of PK data into efficacy models to optimise outcomes and ‘humanisation’ of PK/dosing
    • Correlation of exposure with efficacy and drug response
    • Magnitude of effect
    • Defining PD drivers and which parameters important to for efficacy
    • Understanding of post-antibiotic effect (PAE)
    • Mathematical modelling of data
  • ADME/PK profiling specific to the development of anti-infectives
  • Bioassay/ bioactivity drug quantification
  • Development of bespoke PK models and assays with drug quantification in multiple tissues/sites
  • Tolerability assessment of new compounds utilising multiple endpoints

Hollow Fibre Infection Model (HFIM) PK/PD platform

  • Rapidly expanding facilities for in vitro PK/PD analysis in the HFIM
    • Dedicated HFIM laboratory space at BSL2 with four tall double incubators and 52 pumps
    • Up to 30 cartridges (depending on model type and duration) can be run in parallel for different organisms, variable drug infusion and clearance rates with study duration from hours to 6 weeks; capacity is still increasing
    • A team of scientists trained in setting up and running the system
    • Full microbiology support 
    • BioA facilities for LC-MS analysis of PK samples 
    • A dedicated PK/PD modelling team
  • Significant experience in establishing models and performing studies
    • Development of new infection models using reference or clinical isolates of different bacterial species
    • Mathematical modelling to establish experimental parameters required to mirror human or animal PK profiles in single- and multi-drug studies
    • Combination studies with up to four individual compounds
    • Dose-response and dose-fractionation studies to determine pharmacodynamic driver and magnitude of effect
    • Resistance generation studies/mutant prevention window identification and mechanism of resistance 

In addition to specific anti-infective capabilities, Evotec’s highly accomplished drug discovery platform including high-throughput screening, structure-based drug design, medicinal chemistry, bioinformatics research, proteomics, and biomarker and reagent production platforms can also be accessed to support and accelerate anti-infective drug discovery programmes.

Summary

  • Expertise with multiple classes of anti-infective agent including small molecules, natural products, peptides, antibodies, other biologics and vaccines
  • Extensive platform for target identification, validation, and resistance determination/ characterisation
  • EvostrAIn™ – An extensive range of geographically diverse human pathogenic bacteria and fungi covering isolates susceptible and resistant to current antimicrobial drugs
  • Broad range of in vitro methods for screening, compound profiling and MOA determination
  • Delivering rapid proof of concept and detailed in vivo characterisation through a comprehensive range of established pre-clinical models encompassing bacterial, fungal, viral, and parasitic infections
  • Clinical translation via tailored in vitro and in vivo pharmacology and biomarker solutions
  • Exploitation of HFIM PK/PD platform for in vitro humanised drug exposure studies and PK-PD profiling

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