Gram-Negative Antibiotics – Drug Discovery Case Study

October, 2017

Auspherix and Domainex worked together to develop a novel class of gold(I) antibiotics, with a broad spectrum antibacterial activity against the so-called ESKAPE pathogens.

Bacteria have become increasingly resistant to existing antibiotics and the spread of drug-resistant bacteria has become a significant issue. It is estimated that 50-60% of hospital-acquired infections (HAIs) in the U.S. are caused by antibiotic-resistant bacteria including the so-called ESKAPE pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa & Enterobacter spp.). The discovery and development of new antibiotics has slowed in recent decades and no novel class of antibiotic has been brought to the market in >30 years. The World Health organisation (WHO) has stated that humanity is facing the prospect of returning to a pre-antibiotic era in which common infections and minor injuries could be lethal. There is consequently a significant need for new antibacterial agents especially against Gram-negative bacteria.

Hit identification: Following phenotypic screening of a library of FDA-approved drugs, Auranofin, a second generation chrysotherapy agent was identified as having activity against Gram-positive bacteria.  Auranofin is a linear, 2-coordinate gold complex which was approved for the treatment of rheumatoid arthritis as a disease modifying antirheumatic drug (DMARD) in 1985.   

Lead Optimisation: Three key areas of the Auranofin structure have been investigated during structure activity relationship (SAR) studies: Linker (X), Ligand (R) and the Phosphine group.  Early findings indicated that both Gold and Phosphine are required for antibacterial activity.

The phosphines have been extensively investigated with the size and lipophilicity of phosphines shown to have a critical role in determining activity against Gram negative pathogens. The most active phosphines sit within a defined physicochemical space which Domainex medicinal chemists continue to explore and refine.

Investigations have also shown that in combination with an optimal phosphine, a variety of linker (X) and ligand (R) combinations are well tolerated and exhibit broad-spectrum activity.

Synthetic method development: Synthesis of lower alkyl phosphines is not trivial so medicinal chemists at Domainex have developed robust synthetic routes to provide access to novel phosphine ligands. The synthesis of each series proceeds via a common gold(I) chloride intermediate, and syntheses on multi-gram scale have been performed with great success.

Assay development: Metal complexes have intrinsic reactivities essential to their biological effect which adds complexity to in vitro and in vivo profiling.  Domainex’s analytical team have successfully developed an extensive range of novel in vitro assays for triaging gold(I) complexes, and established novel analytical methods for the analysis of surrogate markers of parent complexes in vivo.

Conclusions:

A novel class of gold(I) antibiotics have been developed, with broad-spectrum activity against the so-called ESKAPE pathogens

Three distinct chemical series have been identified and the specific structure of the phosphine ligand is a critical determinant of Gram-negative activity.

Following systemic dosing in rodents, compounds show activity in plasma and urine ex-vivo bioassays.

Five patents have been filed with Domainex scientists names as inventors

‘The full integration of the Domainex scientists into the project team has been crucial.  They have shown real commitment to the project and have been instrumental in helping solve a number of key scientific challenges we have faced over the last 2-3 years.  Their passion to do the very best science and to help to achieve the project’s objectives has been clear from the very start.’ 

Dr Neil Miller, CEO Auspherix

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