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AMR: Now More Than Ever

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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