Science Pool

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.

WATCH OUR WEBCAST TO LEARN MORE

Date: July 24th-29th, 2022

Venue: Renaissance Tuscany Il Ciocco, Lucca | Barga, Italy

Attendees: Alastair Parkes, Stephane Vandenbeele, Guiseppe D'Angelo, Florian Marro

Evotec will be sponsoring the New Antibacterial Discovery and Development Conference, as well as showcasing its research on-site in Italy.

Our scientific program

Presentation

Using Probabilistic Approaches and AI/ML to advance antibacterial drug discovery projects

Alastair Parkes, VP Head of Department III, Medicinal Chemistry

Wednesday, 27 July | 11.30 am - 11.50am

Poster Presentation

Intracellular Staphylococcus aureus replicative dynamics monitoring under antibiotics challenges: highlighting persisters.

Florian C. Marro, Research Associate, Mass Spectrometry & Phenomics

Poster Sessions are scheduled 4:30 pm - 6:00 pm from 25-28 July 2022.

If you wish to meet with us in Italy, get in touch via the form below, we will be happy to arrange a meeting.

Learn more about the GRC - New Antibacterial Discovery and Development.

Don't miss our educational webinar. In-house expert, Ellenia Bordini, will cover various early stage "alternative approaches" for the evaluation of metabolites in human and preclinical species, and how these can be used to direct preclinical safety testing for regulatory submission. 

Take a Ride on the Evotec "Data-Driven R&D Autobahn to Cures"

5 Virtual Sessions over 5 Days

Date: 6 - 10 November 2021 Online | 9 - 11 November 2021 Fiera Milano

Location: Virtual

• Learn how Evotec is using data and science across treatment modalities to accelerate innovation in the area of precision medicine to deliver enhanced speed, lower cost, and predictive efficacy

• Find out about our efforts in AI/ML in the design and development of both small molecules and antibodies, the importance of  biomarker development, targeting RNA, and our approaches to target validation

Day 1:
Drug Discovery in Evotec Multiverse: Knowledge-driven Integrated R&D

Presented by: Adam Davenport, Tim James and Christophe Boldron
When | Monday 6 December @ 11am EST | 8am PST | 4pm GMT | 5pm CET

Day 2:
The Importance of Precision Medicine: How Biomarkers Optimise Translation from Bench to Bedside and Back

Presented by: Elizabeth van der Kam, Christoph Schaab
When |Tuesday 7 December @ 11am EST | 8am PST | 4pm GMT | 5pm CET

Day 3:
The Early Bird Catches the Helix: Expanding the Druggable Target Space to RNA

Presented by: Steffen Grimm, Hilary Brooks
When | Wednesday 8 December @ 11am EST | 8am PST | 4pm GMT | 5pm CET

Day 4:
Do Firefighters cause Fires? Establishing Real Disease Associations through Target Validation

Presented by: Hauke Cornils, Susan Boyce
When |Thursday 9 December @ 11am EST | 8am PST | 4pm GMT | 5pm CET

Day 5:
Translate your Idea into Product: AI-Driven Antibody Discovery at Evotec

Presented by: Barbara Bachler-Konetzki, Randal Ketchem, Maria Pilla
When | Friday 10 December @ 11am EST | 8am PST | 4pm GMT | 5pm CET

Each session will take approx. 45 min including Q&A. You will need to register for each day separately to reserve your seat.

RESERVE YOUR SEAT

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

In this review article, we provide the latest insights into de novo design approaches based on  artificial intelligence (AI) algorithms with a specific focus on ligand-based methods.

It includes:

• a background to de novo design approaches developed prior to the use of AI
• an overview of AI and commonly employed neural network architectures used in ligand based de novo design
• a list of more than 100 deep generative models reported in the literature from 2017-2020
• current applications of deep generative approaches in the drug discovery context
• an insight into future applications of deep generative models in de novo drug design 

LEARN MORE

Date: 18th November 2021

Venue: Virtual

Attendee: Dr Alastair Parkes, Group Leader at Evotec will be presenting on "Novel LpxA inhibitors targeting Pseudomonas aeruginosa"

Learn More About the EADA Conference