LONDON – Going back to the roots of antibiotic discovery, a new Oxford University spinout has turned to natural product libraries to uncover recurring motifs that can be translated into novel synthetic chemistry.

The approach of reducing natural products to their skeletal cores and building around them was used decades ago during the development of penicillins but fell out of fashion with the rise of combinatorial chemistry and high-throughput screening.

Going back to the tried and tested method has resulted in a 500-strong library of qualified compounds and a lead program with a new mode of action against a multidrug-resistant gram-positive pathogen.

Now the company, Oxford Antibiotics Ltd., is looking to raise £3 million (US$3.8 million) in seed funding to take this lead, OxAb1, into clinical trials and to further validate other compounds that have shown activity against gram-negative bacteria and drug-resistant fungal pathogens.

"I'm slightly embarrassed to say we don't have an entirely new approach and that our research is based on natural products," said Mark Moloney, founding scientist. "But this was successful in the past, before being abandoned by pharma as a whole in favor of a target-driven approach which has been singularly unsuccessful," he told BioWorld Today.

Oxford Antibiotics' compounds are based on tetramates, the bioactive core skeletons found in a range of antibacterial natural products.

The initial spur was finding that tetramates are a pervasive structural feature. "Time and time again we came across natural products that had this element. We thought it was interesting, prompting us to use them as the basis of a compound library," said Moloney.

Tetramates do not themselves have potent antibiotic properties, but Moloney, who began his research at Oxford University in 1985 working on penicillin biosynthesis, has devised ways of generating chemical diversity around those scaffolds.

The synthetic chemistry came before any investigation of possible biological effects. With grant funding, Moloney built an initial library of 13 compounds, subsequently extending it out to more than 550 compounds in a collaboration with an industrial partner, Galapagos NV.

"Of these, large numbers turned out to be quite active against gram-negative bacteria, though they were less so against gram-positive," said Moloney.

The in vitro activity of the antibacterial compounds is as good as any marketed antibiotics. "This looked very promising. We had a large number of active compounds with a strong indication of what was required in terms of chemistry to shape them into drug candidates," Moloney said.

Now the research has reached the limits of public grant funding and private capital is needed to move things on, prompting the spinout of Oxford Antibiotics. There are some offers on the table for the seed round, but not as yet for the full £3 million.

Apart from accessing private capital, forming the company enables it to secure the intellectual property. Tetramates are not only attractive for their chemical properties, but also because the patent landscape is uncluttered, a factor Moloney said he believes will be important to investors down the line.

Biotech veteran Alex Pretsch is CEO designate. "He is experienced in antimicrobial science and is a serial entrepreneur, who brings great experience," said Moloney.

Moloney, too, has experience in spinout formation, providing the scientific foundations for Oxford Advanced Surfaces plc, which specializes in modifying the surfaces of plastics, composites and carbon-based materials to introduce activity into inert surfaces.

TETRAMATE TARGETS

Starting with the chemistry and then investigating which biological targets are involved has the advantage that unknown targets could come to light, or that previously undruggable targets are addressed.

At the same time, it is known in advance that a compound can readily be synthesized and manufactured at scale. "We know we can make it; this is not necessarily the case with naturally derived products," Moloney noted.

On investigation, Oxford Antibiotics' compounds were found to exhibit both classic and unexploited mechanisms of action.

They target RNA polymerase, topoisomerase and gyrase, but also show activity against undeca pyrophosphate synthase (UPPS), a known but previously undruggable target that is involved in lipid biosynthesis in the cell wall. "There has been a great interest in finding selective inhibitors for UPPS," Moloney said.

The tetramate-based compounds do not all function in the same way. Some inhibit all four targets, others two. "For some, we don't know the mode of action, so possibly there are novel targets," said Moloney.

The subject of dual-targeted antibiotics is being discussed in the literature currently. "We think the ability to inhibit two metabolically independent pathways is important, giving bacteria much less opportunity to develop resistance," Moloney said. However, there also are concerns that inhibiting too many key metabolic pathways would cause toxic side effects.

Moloney has been investigating how to make tetramate-based compounds effective against gram-negative bacteria, theorizing that the hydrophobic compounds need to be hydrophilic to penetrate the bacterial cell wall.

"We have done some modifications, and following this, have seen weak gram-negative activity. We think that validates the hypothesis and we will have a go at further optimization," he said.

All of the above is the result of 10 years of basic chemistry research at Oxford University. "The last decade has been about developing understanding of the technology and understanding the nature of the compounds," Moloney said.

There are now 12 compounds that are ready for putting into the bottom end of the drug discovery pipeline, with the lead OxAb1 around three years from the clinic.

The backdrop to his research was depressing, with pharmaceutical companies deserting the field. Moloney said, "It has not been good, but with antimicrobial resistance [AMR] starting to attract international attention, the upswing is just starting."

AMR is a multifaceted problem, and there is a danger that the requirement to develop new drugs is overlooked in efforts to curb use, improve infection control and develop new diagnostics.

Now is the right time to be getting on with the science, in order to ensure the programs are in shape once finance from international initiatives to spur antibiotic innovation becomes available, said Moloney.

"We believe that by forming Oxford Antibiotics now, and getting on with the programs, we will be in a good position in 18 months when the situation is improving.