Science Pool

Download this fact sheet to learn more about Evotec's anti-infectives virology platform including: 

• Full integration
• Project based flexibility tailoring
• Development of novel tools

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Learn more about fighting tuberculosis by targeting the essential enzyme PptT.

Together with collaborators at Weill Cornell Medical College, Texas Agricultural and Mechanical University (TAMU), and  University of North Carolina (UNC), we identified the amidinourea compound AU8918, through a phenotypic screen, as an interesting anti-TB compound. We went on to identify its target within Mycobacterium tuberculosis, as phosphopantetheinyl transferase (PptT) - an essential enzyme involved in synthesis of cellular lipids and virulence factors.

This paper describes:

• Next steps taken in further pursuit of this novel anti-TB series
• An expanded collaboration within the TB Drug Accelerator consortium
• Latest structure guided SAR exploration around AU8918 for more potent and safest Lead-like analogs

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Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence.

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Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). In this recent article, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus

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Chikungunya virus, which is transmitted by mosquitoes, can cause disabling chronic arthritis. There are currently no medicines for prophylaxis of Chikungunya, or other viruses transmitted by Aedes mosquitoes, such as Dengue and Zika. Potential therapeutics have been identified, but to perform a successful chemoprophylaxis trial during a short Chikungunya outbreak requires an identified at-risk population. We examined the potential for application of a household transmission model, as used in testing prophylactic drugs against respiratory viruses, included influenza and COVID-19.

In this poster we:

• Set out the evidence for multiple Chikungunya infections occurring per household
• Describe how we are validating the secondary household infection rate
• Show how this could be used in future clinical trials to demonstrate prophylactic efficacy against chikungunya virus infection and other Aedes-mosquito-borne viruses

Read our poster to learn more about our research!

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This article forms a book chapter in Artificial Intelligence in Drug Design.

In this review article, we provide the latest insights into fighting COVID-19 with technologies such as artificial intelligence.

It includes:

• an overview of the ongoing demand for efficacious drugs to treat potential vaccine-resistant COVID-19 variants in the future
• how identifying and repurposing marketed drugs for the treatment of COVID-19 plays an important role in this process 
• how artificial intelligence can be employed to speed up the drug discovery process by facilitating the selection of potential drug candidates as well as monitoring the pandemic and enabling faster diagnosis in patients
• a focus on the impact and challenges associated with artificial intelligence for drug repurposing of therapies for the treatment of COVD-19

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The Covid-19 pandemic is a stark reminder that infectious diseases and their sometimes devastating effects will always have to be reckoned with. However, beyond Covid-19 a second global health crisis is emerging, and it is imperative that we act now to prepare for the increasing development of antimicrobial resistance (AMR) towards our currently existing arsenal of antibiotics.

The key to de-risking and expediting the development and approval of new antimicrobials is a detailed understanding of the relationship between the fate of the antimicrobial compound in the body: pharmacokinetics (PK), and the impact of exposure to the compound on the target microbe: pharmacodynamics (PD). This understanding is essential for development of optimal human dosing regimens, maximising efficacy and minimising the emergence of resistance. Only with this understanding will we mitigate the risk of clinical trial failure, and ultimately extending the clinical utility of a new antimicrobial in the face of increasing AMR.

Among the several non-clinical in vivo and in vitro models of infection which provide complementary information to understand this PK/PD relationship, the in vitro Hollow Fibre Infection Model (HFIM) is the most versatile. Evotec’s comprehensive HFIM capabilities combined with its drug development expertise and unique EvostrAIn™ collection of microbial pathogens provide a versatile in vitro PK/PD platform to de-risk and accelerate the development of antibacterial, antifungal and antiviral compounds.

The Hollow Fibre Infection System consists of two principle compartments:

1. a central reservoir and associated tubing, which constitutes a circulating system, and
2. a hollow fibre cartridge consisting of thousands of hollow permeable capillaries, or fibres, housing the bacteria, fungi or virus of interest

The HFIM is a dynamic model that is able to simulate almost any given concentration-time profile for an antimicrobial compound or combination of compounds, without the constraints of animal PK. The containment of the bacterial in the peripheral compartment of the hollow fibre cartridge means the system is able to simulate PK profiles with no bacterial cell washout. It is also suitable for simulated dose range fractionation studies and can determine resistance prevention exposure for any simulated PK profile. Combining the ability to run long-duration experiments with multiple drug infusion profiles means that the HFIM is especially well suited to the development of antimicrobial combination therapy against slowly replicating bacteria such as Mycobacterium tuberculosis, a view which is supported by the European Medicines Agency (EMA).

When should the Hollow Fibre Infection Model be used in the drug discovery process?

• Early screening of compounds can de-risk future HFIM experiments.
• Studies at the pre-clinical stage (pre-IND) will help to improve understanding of the PK/PD relationship. This is particularly important if an animal model is not available, or if the animal can’t tolerate the inoculum levels that need to be tested for example in resistance studies.
• During clinical development the HFIM can help to inform trial design. Hollow fibre studies can be performed based on human exposure data to address discrepancies between clinical and pre-clinical findings.
• Even after drug approval the HFIM can be used to expand the label or optimise the dosing regimens.

Evotec has established HFIM capabilities in state-of-the-art containment level 2 facilities, with a growing team of dedicated Hollow Fibre specialists. Providing full microbiological support to projects and aided by specialist bioanalytical and mathematical modelling and simulation teams, Evotec can offer a bespoke in vitro PK/PD service tailored to advance individual antimicrobial development programmes.

Learn more about Evotec's Hollow Fibre Infection Model by downloading our white paper

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The Covid-19 worldwide pandemic unveiled extraordinary resources within the scientific and pharmaceutical community delivering vaccines and therapeutic drug candidates within timelines never seen before. While the pandemic hit suddenly and the number of cases increased exponentially, the AMR crisis remained silent. Nevertheless, it is progressing and the emergency and spread of multidrug resistance is putting our existing antibiotic arsenal under increasing threat.

Is AMR our next pandemic?

Possibly, if we continue to consider antibiotics as fire-extinguishers: and only create novel therapeutics once we are face to face with the fire.

Innovation and collaboration are key in the preparedness, together with expertise and operational excellence. Evotec, with more than 200 scientists dedicated to antibacterial drug R&D, is at the forefront of AMR research and innovation. With infectious disease platforms spanning from in vitro biology to in vivo pharmacology and medicinal chemistry and benefiting from HTS platforms, ADME and toxicology expertise.

Innovative thinking and creativity to discover novel antibacterial compounds begins with designing a strategy to discover novel active compounds. By changing the paradigm in phenotypic screening and developing the Vivo Mimetic Media (VMM) concept for discovering novel Gram-negative antibacterials, Evotec has validated five alternative bacterial culture media that better mimic the conditions bacteria are facing during infections. These VMM conditions are affecting the physiology of growing bacteria by altering permeability (porins, efflux pumps and outer membrane) but mainly unveiling new targets and mechanisms of action (MoAs).

The cornerstone of innovation in antibacterial drug discovery is the application of machine learning to optimise chemical matter. By combining biological data, medicinal chemistry expertise and a deep learning approach, Evotec has enabled the prediction of antibacterial activities against 15 bacterial strains and provided de novo design of compounds, 76% of which were accurately predicted for their activity.

Validation of active compounds in appropriate pharmacodynamic models is crucial, while innovative approaches are needed for tailored design and improved readouts. By using luminescent or fluorescent bacteria, infection models with higher complexity have been developed to evaluate the spread of infection in real time and most importantly, measure the distribution of the active compound fluorescently labelled to the site of infection.

Innovation through collaboration and partnership is at the forefront of Evotec’s unique business model. Through a highly strategic partnership between Evotec, Resolute Therapeutics and CARB-X, a new antibacterial drug class termed TriBe is being advanced in the preclinical pipeline, with the objective to bring a candidate for the treatment of cUTI, cIAI and lung infections to clinical phase I. The TriBE series have unique properties with nanomolar bacterial topoisomerase inhibitors binding via the GyrB/ParE subunits, very broad bacterial spectrum, low potential to select for resistance, favourable PK and in vivo efficacy in multiple models of infection have been demonstrated.

While a consensus exists on the real and clear need for new antibacterials and approaches, the challenges are numerous and complex. Innovative thinking, creativity and novel approaches (target and technology) underpin anti-infective drug discovery at Evotec, enabling the redesigning of antibacterial discovery infrastructure to ensuring an integrated approach and foster collaboration, partnership, training and cross-interaction.

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The key to de-risking and expediting the development and approval of new antimicrobials lies in the detailed understanding of the PK/PD relationship. Understanding this relationship informs the development of optimal human dosing, maximising efficacy while minimising the potential to antimicrobial resistance.

This white paper describes and appraises today's most versatile in vitro system for the determination of in vitro PK/PD relationships between antimicrobial compounds and bacteria, fungi and viruses - the Hollow Fibre Infection Model (HFIM)

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Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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