LABORATORY INFORMATICS g
Puerta. ‘This has given our company and its platform – Blacksmith – their distinctive names; we are 21st century blacksmiths, working with metals to design new medicines.’ The platform starts by selecting chemical groups that are optimised to bind to a specific metal- protein combination and then ‘grows’ these into a computer model of a lead compound.
About 30 per cent of all known
enzymes depend on metal ions and could, theoretically, form targets for Forge’s bio-inorganic, computational and medicinal chemists to work with. They have chosen a zinc enzyme known as LpxC, that catalyses an essential step in the synthesis of the Gram-negative cell wall. This enzyme has been investigated as an antibiotic target for about 10 years, but research has not yet produced any viable drugs. ‘Using Blacksmith, we have designed a completely novel LpxC inhibitor that binds to the zinc ion in the active site; it works well in mice, and we hope that it will enter clinical trials in 2020,’ says Puerta. Like Oxford Drug Design, Forge is aiming to test the new molecule in urinary tract infections caused by drug- resistant Gram-negative bacteria.
The role of computational chemistry in discovering new medicine These are examples of the innovative small companies spun out from academic labs that are currently making most of the running in antibiotic development, stepping into a gap left by big pharma companies when they largely abandoned unprofitable antibiotic pipelines. Others with a computational focus include Seres Therapeutics, which uses genomics and systems biology to characterise the community of microbes found in our intestines to design tailored therapeutics resistant Clostridium difficile infections of the gut. And, at last, substantial funding is being made available for these small companies. Oxford Drug Design has attracted funds from the EU and from the UK government via Innovate UK; Forge and Seres were among the first 24 companies to receive funds from the CARB-X initiative, which plans to invest almost half a billion dollars over five years in combating the most resistant pathogens. The CARB-X funders – the US
Department of Health and the UK’s Wellcome Trust – provided this funding in the hope of seeing at least 20 truly novel products entering the world’s armoury against resistant bacteria. However, these products will not all be drugs. Resistance is an unstoppable, natural phenomenon, and resistance to even
20 Scientific Computing World August/September 2018
typhoid fever. The variant that causes typhoid, Salmonella enterica serovar Typhi, is only one of several subtypes that have evolved to break out of the human gut and cause systemic disease. Nicole Wheeler, a postdoc at the Sanger Institute, has used a random forest-based machine-learning method to classify many independently evolved S. enterica strains and built a classifier that can precisely place any variant on a scale from the relatively benign to the most invasive. ‘Interestingly, we found that the invasive
”What makes our computational platform unique is the specific focus on understanding and simulating the properties of the metal and its interactions with the protein target and candidate drug molecules”
the ‘best’ antibiotic (however that is defined) is bound to develop sooner or later. Ideally, we need the widest possible variety of antibiotics with different targets; some can be effective against many kinds of bacteria, but these should be complemented with narrow-spectrum drugs that target only one or two. And these specialised drugs must be used alongside rapid, accurate diagnostic tests. CARB-X is as interested in funding diagnostics as in drugs. Developing accurate diagnostics depends on a deep understanding of microbial genetics, genomics and evolution. The Wellcome Sanger Institute near Cambridge, UK, has been a centre of excellence for human and microbial genomics for 25 years. Rapid, large-scale sequencing and detailed analysis of bacterial genomes is enabling scientists based there to explain how bacteria adapt to different environments and how resistance arises, with implication for the design of diagnostics, vaccines and drugs. Two recently published studies from this institute illustrate the important role that genomics plays in the battle against drug resistance. Many, but not all, variants of Salmonella enterica cause disease, ranging from painful but short-lived food poisoning to potentially dangerous
strains were the least genetically complex’, she says. ‘The metabolic pathways that have enabled S. enterica to adapt perfectly to their natural environment – an inflamed human gut – are not as important for invasive strains, so they have been allowed to degrade.’ Wheeler and her co-workers are now adapting their algorithms to discriminate between antibiotic-resistant and susceptible strains. Typhoid fever is widespread in low- and
middle-income countries. Most cases respond well to antibiotics, however, and the case fatality rate has fallen from 15 per cent a century ago to 1 per cent today. There is no room for complacency,
however, as resistant strains are becoming more common, potentially threatening the return of typhus as an untreatable disease. Towards the end of 2016, a group of researchers at the Sanger Institute, including postdoc Elizabeth Klemm, came across reports of a strain in Pakistan that was resistant to almost all antibiotics except azithromycin, the so-called ‘drug of last resort’. They sequenced this ‘extensively drug resistant’ (XDR) strain, compared the sequences to a database of known resistance genes and discovered that the bacteria had acquired new resistance genes through horizontal gene transfer. This data may one day be useful in drug development, but only if rapid diagnostic tests that are precise enough to pinpoint the specific variant involved in an outbreak can be readily available. These case studies highlight some of the computational tools that are now available to help human scientists outwit bacterial genes. There are bound to be many more, but progress remains slow. And even when the novel drugs and diagnostics have entered clinical use, they will only form part of the solution. We also need to preserve and conserve the antibiotics we still have, and there everyone has a part to play.
Dr Clare Sansom is a freelance science writer, senior associate lecturer at the University of London where she teaches MSc bioinformatics for Birkbeck College. Dr Sansom also teaches medicinal chemistry at the Open University.
@scwmagazine |
www.scientific-computing.com
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