Sharing expertise to develop a new class of antibiotics
Combining medicinal and computational chemistry with organic synthesis expertise to create a new class of antibiotic compounds based on boronic acids.
The Challenge
The issue of antibiotic resistance as a concern is well acknowledged globally. Through a KTP scheme in collaboration with the University of Sheffield, AF ChemPharm applied advanced in silico techniques to identify a number of potential pharmacophores as next-generation antibiotics. AF ChemPharm, through a KTP scheme in collaboration with the University of Sheffield, using advance in sillico design identified a number of pharmacophores as a new generation of antibiotics. Synthesis and initial testing of these compounds showed activity against a number of bacteria, and currently, lead-optimisation is being pursued.
The problem of resistance stems from the fact that bacteria have developed a range of protective mechanisms to remove, deactivate or overcome the toxicity of antibacterial agents. They rely on different genetic resistance mechanisms, e.g. acquisition of an antibiotic-resistant gene from other bacteria by horizontal gene transfer, leading to the spread of antibacterial resistance.
The Approach
AF ChemPharm engaged with antibiotic discovery through a KTP program with the University of Sheffield, working with Prof. Beining Chen (Department of Chemistry) and Prof. Peter Willett (Chemoinformatics). Building on some results from a previous three-year prestigious Marie Curie European grant (a trilateral collaborative project in association with the National University of Ireland, and a Swiss biotechnology company), the company recognised the need to move away from traditional antibacterial drugs that are mainly based on naturally occurring antibiotics. Based on AF ChemPharm’s experience and expertise in the synthesis of boronic acids, and the fact that they offer a new and potent inhibitory effect against penicillin-binding proteins, this class of compounds was selected to study potential antibacterial agents as a promising new strategy in a combined therapy approach to fight bacteria resistance mechanisms.
In silico computer modelling tools were utilised to design a small family of molecules via fragment-based screening. These molecules were predicted to bind strongly with penicillin-binding protein 3 (PBP3), while exhibiting drug-like properties based on the well-established Lipinski’s rule.
In silico computer modelling tools were utilised to design a small family of molecules via fragment-based screening. These molecules were predicted to bind strongly with penicillin-binding proteins 3(BPP3), while exhibiting drug-like properties based on the well-established Lipinski’s rule.
The Results
The study identified four compounds to synthesise and test test, of which one showed in vitro bioactivity. One initially synthesised, showed bioactivity. Preliminary test results for this compound show effective inhibition of Pseudomonas aeruginosa at approx 31 μg/mL (0.07 μmol), providing a pivotal foundation for further research.
We developed a synthetic route to our target compound, however robust and scalable paths remain a challenge. Robust and scalable synthetic paths, however, remain a challenge. We aim to build on this work by developing the synthesis of the predicted pharmacophores via a common intermediate to allow easy access to analogues.
The opportunities from this collaboration are to synthesise target small molecules, conduct tests on their efficacy preventing bacterial growth and, via lead optimisation process, potentially develop a drug candidate as a formidable antibiotic.
This is a project that forges expertise from different disciplines essential to pursue the task of drug discovery. It also strengthens collaboration between an SME and a highly accredited Russell Group university to fill an urgent therapeutic need.
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