Structure-based target exploration for the discovery of new leads for antibiotics

There is no doubt that there is an urgent need for new antibiotics. We have to act now if we want to avoid being thrown back into the dark ages of medicine where many bacterial infections ended deadly. In this project, we are exploring three different targets for new antibiotics. Using computational methods, these targets were predicted to bind drug-like molecules with high affinity, and, very crucial, these molecules were also predicted to have the desired properties to reach the targets in the bacteria. We will use experimental and computational screening methods to discover molecules blocking the functions of the targets and such potentially killing the bacteria. Subsequently, the molecules will be optimized to be more potent and less toxic. To achieve this goal, we have assembled a team of highly skilled researchers from Norway and India which are experts in molecular design and chemical synthesis. So far, we have worked on the targets PanK, FabF, and FabB. For all targets, fragment screenings have been conducted and a number of hits have been obtained. Our Indian collaborators have synthesized analogues of the hit compounds with the goal to improve their affinities. The Bergen team has determined a number of crystal structures of the hit compounds in complex with their targets to support the optimization of the compounds. We have also obtained some funding from other sources to continue compound optimization after the end of this project.

In this project, we have worked on three targets for antibiotics against P. aeruginosa: PanK, FabB, and FabF. For all three targets, we have determined crystal structures in complex with inhibitors. Further, we have developed binding assays for all targets and identified fragment hits. Our partners at the CSIR-Indian Institute of Chemical Technology have initiated synthesis to optimize some of the hits. Unfortunately, this has not yet resulted in potent compounds. However, the generated data package constitutes a very valuable foundation upon which more potent inhibitors can be developed in the future and thus can contribute to deliver new antibiotics which are urgently needed to prevent a looming medical crisis.

There is no doubt that there is an urgent need for new antibiotics. While better surveillance systems for antimicrobial resistance and antibiotic use as well as modified treatment strategies will probably prolong the lifetime of some antibiotics, resistance development will be unavoidable in the long run. The proposed research will deliver starting points to form the basis upon which new treatment options can be developed. To reach this goal, we have assembled a team of highly skilled researchers from Norway and India which are experts in structure-based drug design and chemical synthesis. Together, we will explore three different targets for antibiotics which were predicted to be druggable and at the same time to bind compounds with the desired physico-chemical property range for antibiotics against Gram-negative bacteria which include some of the most critical groups of resistant bacteria.