LABORATORY INFORMATICS g
to-haves: they are essential’, says Puerta. ‘Without them, there would be next to zero innovation in this space.’ But these developments, however
welcome, have not solved the problem of funding antibiotic development; rather, they have simply pushed the bottleneck further down the pipeline. As Peter Jackson, executive director of the AMR Centre in Alderley Park, UK, says, starkly, ‘the reimbursement side of the market [for AMR (anti-microbial resistance) drugs] is broken: the reward available for antibiotic development and commercialisation falls considerably short of its cost.’ Therefore, even getting a drug to market may not be enough to save a small company. Achaogen, a San Francisco-based biotech, launched its aminoglycoside antibiotic, plazomicin, onto the market for complicated UTIs in 2018; less than a year later, it had filed for Chapter 11 bankruptcy. The main reason the current economic model of drug development is broken when applied to antibiotics is the way in which they must be used. A novel antibiotic is not like a new drug for arthritis or heart disease, with an immediate potential market of millions of patients. Bacteria can develop resistance to new drugs as soon as they are exposed to them, so it makes sense to keep novel drugs back until others fail. A new antibiotic is more like a new fire extinguisher, bought to hang on the wall until a fire breaks out. And convincing companies – particularly risk-averse big pharma – to take a drug through expensive clinical trials to, perhaps, sit unused on a shelf for years, is understandably difficult. Among the few larger companies
with serious antibiotic pipelines are the Japanese company Shionogi, which is partnering with the AMR Centre to take a novel antibiotic to Phase III trials, and Basilea, based in Basel, Switzerland, which has formed a close collaboration with Forge. Such companies are forward- looking enough to realise how badly the spread of antibiotic resistance might affect their work in other therapeutic areas. And Jackson has noticed that some companies are beginning to re-brand antibiotic development, for example positioning drugs for recurrent lung infections in their respiratory franchise. ‘We now often refer to AMR drugs, rather than antibiotics, to try to emphasise these targeted cross-relationships with other disciplines,’ he adds. Encouraging as such large-company
initiatives are, they can only ever provide a partial solution to the ‘broken’ antibiotic pipeline. So-called ‘pull’ incentives for
18 Scientific Computing World December 2019/January 2020
“With the economic state of antibiotic development, ‘push’ mechanisms for antibiotic programmes aren’t nice-to-haves: they are essential”
antibiotics – de-linking reimbursement from sales volumes by, for example, providing a substantial reward at the point a drug is licensed or using a subscription model – will be just as necessary as the ‘push’ incentives provided by Carb-X and translational support offered by the AMR Centre. There are few incentives.
Open source alternatives Matthew Todd, a professor at the UCL School of Pharmacy, London, set up a radical, open source alternative to commercial drug development when he was at the University of Sydney, initially concentrating on malaria and neglected tropical diseases. This is a collaborative approach, using a similar model to Wikipedia: all contributions are voluntary, all information and results are kept freely available, and anyone with knowledge and skills is welcome to share them. Such an open source project may start
from the screening of libraries of large numbers of molecules against validated target proteins using both in silico and in vitro methods, with all results deposited in open, online lab notebooks. ‘This approach can bring anyone on board, even young students in high school chemistry classes and their teachers’, says Todd. His first antimicrobial open source project is a pilot one with a novel target:
bacterial proteins in the Mur ligase family. These are enzymes that catalyse the reactions that string together amino acids to make the cross-links stabilising bacterial cell walls. ‘These enzymes are great targets’, says Todd. ‘Just like a penicillin, a Mur ligase inhibitor would break up the bacterial cell wall, killing the bacteria. Crucially, humans have no cell walls, so the drugs should, if we’re lucky, have few side effects.’ Two pharma companies set up drug discovery programmes targeting Mur ligases, and both were stalled, so this area is surprisingly little explored. Todd set up the Mur ligase project with
Warwick microbiologist Chris Dowson, Frank von Deflt’s group at Diamond Light Source and cheminformatics specialist Chris Swain. It involves solving crystal structures to locate small chemical fragments bound to active sites of Mur enzymes, with docking and cheminformatics tools to elaborate and build on hits. ‘We have found some interesting molecules but are looking for new compounds to screen, and further cheminformatics tools to help with docking and compound elaboration, particularly straightforward ones for chemists who are not experts in this area to learn,’ says Todd. Making results available without patent
protection should, again, lead to time and cost savings compared to conventional early-stage drug discovery. But no drugs developed this way have made it to the clinic. It is too early to gauge how effective this new paradigm will be in fixing the broken antibiotic pipeline. It is all but certain more complementary approaches will be needed.
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