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Commentary – New Models Needed for Antibiotic Resistance

MRSA bacteria

Scanning electron micrograph of methicillin-resistant Staphylococcus aureus, or MRSA, in brown spheres, surrounded by cellular debris. (NIAID, NIH)

26 Dec. 2019. Readers of yesterday’s New York Times woke up to disturbing news of difficult science and failing business models for stemming the scourge of infections resistant to antibiotics. Solving this vexing problem may take a different way of treating infections, with a new type of business to develop and produce the treatments.

Yesterday’s story reveals more of a business than scientific failure. Times health and science reporter Andrew Jacobs tells about antibiotic drug makers going bankrupt even as some products show promise against drug-resistant bacteria. And even with government contracting for these new antibiotics, venture investors are reluctant to bankroll developers of these new drugs, preferring bigger payoffs from treatments for chronic disorders like cancer and heart disease.

Yet as the story also notes, the science of finding new antibiotics isn’t getting any easier. Jacobs reports that in the last 20 years, only two new classes of antibiotics have reached the market, with most new drugs designed as variations of current drugs. And the difficult science contributes to a high price tag for developing new antibiotics, as much as $2.6 billion, that’s driving away many pharma companies, leaving only three drug makers today in the antibiotics market.

The story notes that the U.S. government is using its available tools and resources to find a solution. An agency leading this effort is the Biomedical Advanced Research and Development Authority, or BARDA, part of the Health and Human Services department. BARDA supports research and contracts for stockpiles of drugs to prevent or treat public health and bio-terrorism threats, including drug-resistant microbes. The agency also supports an international consortium called the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, or CARB-X to develop new antibiotics. But even with BARDA buying $124 million of its lead drug, antibiotics developer Achaogen, a company with a market capitalization at one time of $1 billion, still went bankrupt.

Precision medicine for antibiotics

One of the reasons for the difficult science and high cost of antibiotics may be the way the drugs designed and made. The goal of many new antibiotics is to find a mechanism that kills the microbe or disables its infecting process. And the more bacteria or fungi the antibiotic can neutralize, the more desirable a product it becomes, both medically and financially. But microbes often evolve quickly to evade these mechanisms, making antibiotic development a constant race against nature to find these silver bullets, requiring continuous R&D, a reason why many investors are reluctant to back antibiotics developers.

This suggests a need for a different approach to fight drug-resistant bacteria and fungi. Many parts of a new model for fighting antibiotic resistance are in development, and the pieces still need to be assembled, but the outline of a precision-medicine rather than mass-produced drug model is beginning to emerge.

In January, Science & Enterprise reported on a lab at Johns Hopkins University that uses genomic sequencing to identify vulnerabilities in a bacterium’s DNA. A team led by pathologist and microbiologist Patricia Simner uses a hand-held genomic sequencing device called called the Minion made by Oxford Nanopore Technologies in the U.K. The Minion is a portable disease surveillance system that analyzes DNA from blood samples, returning results in as little as an hour, and operates as a plug-in peripheral on a laptop computer.

The Minion technology forces single strands of DNA through nanoscale pores, which makes it possible to analyze samples in real time. Simner and colleagues found they can analyze the whole genomes of Klebsiella pneumoniae, a gram-negative bacteria associated with pneumonia, blood stream infections, wound or surgical site infections, and meningitis, sampled from 40 patients. And, the team reassembled the bacterial genomes, identifying target genes and mutations for antibiotics, all in about one day, with 92 percent accuracy.

This is a different take on precision medicine, where in this case genomic sequencing identifies vulnerabilities of microbes rather than disease-causing mutations in patients. Nonetheless, it offers precise targets in real patients’ infections for drugs, rather than the trial-and-error approach to treating infections often used today.

Diagnostics, of course, is only a first step in the process. Precise formulations are needed to hit the precise targets identified by the genomic sequencing. In the past two years, we’ve seen rapid advances in computational biology and artificial intelligence applied to drug discovery, many of which we’ve documented on this site.

For antibiotics in particular, we reported in October 2018 on biochemistry professors Christophe Corre and Manuela Tosin at University of Warwick in the U.K. that use bioinformatics and the genome-editing technique Crispr to develop a new antibiotic for tuberculosis bacteria. The Warwick team started with naturally-occurring microbes in soil, then altered the genome with Crispr to remove a genetic barrier to produce therapy candidates. The researchers needed several rounds of Crispr editing to find the eventual solution, but the authors say the process can be automated.

One of those rapidly advancing automated tools applied to drug discovery is artificial intelligence, particularly deep learning techniques. In September, we reported on a paper in the journal Nature Biotechnology where researchers from Insilico Medicine in Hong Kong and WuXi AppTec in Shanghai devised deep learning techniques to quickly discover small-molecule drugs. In this case, the researchers discovered potential treatments for blocking an enzyme associated with cirrhosis, or scar tissue in the liver, and other diseases. With this technology, the team discovered drug candidates, ready for validating and preclinical animal testing in 21 days. Later tests with lab animals verified the treatment candidates’ chemical activity.

Small-batch production and distribution

With precision medicine comes a need for smaller quantities of drugs produced on demand, which may not be possible with large-scale bio-reactors that need long lead times. In June 2017, we reported on an initiative by drug maker Eli Lilly and Company, published in the journal Science, about a process for making small quantities of drugs on demand using continuous flow manufacturing processes. The researchers succeeded in producing quantities of a cancer drug as small as three kilograms a day for eight days with techniques that meet current good manufacturing practices. The technology, say the authors, uses advances in chemistry, engineering, analytical science, process modeling, and equipment design.

About a year earlier, we reported on a paper in the journal Nature Communications about a portable, small-batch production unit for biologic drugs. Like chemical compounds, biologic drugs normally need long lead times and are produced in large batches, but Defense Advanced Research Projects Agency, or Darpa, asked a group led by MIT bio-engineering professor Timothy Lu to develop a small-scale bio-reactor. The reactor, measuring 31 x 34 x 36 centimeters, uses microfluidics and a strain of genetically engineered yeast to produce single-dose quantities of two biologic drugs in less than 24 hours.

Fast delivery of small packages in the U.S. is amply demonstrated almost every day, but getting drugs to remote locations is still a challenge. In July, we reported on a project by the humanitarian organization Direct Relief and drone maker and delivery company Volans-i Inc., to deliver drugs needing refrigeration to remote locations. The project team, including drug maker Merck, successfully delivered a drug package in refrigerated boxes between islands in the Bahamas, crossing open water, and well beyond the line of sight of the dispatch team.

A new type of business

Bringing together all of these pieces will likely need a new kind of business, since most of today’s pharmaceutical companies and investors show little interest in antibiotics. We reported in November on a consortium taking shape in Massachusetts that may provide a model for this business. The not-for-profit consortium is made up of companies, universities, and hospitals to create an innovation and manufacturing center in the Boston area for cell and gene therapies. The center is expected to provide lab and production facilities for genome editing, stem cells, and immunotherapies. The goal is to break bottlenecks that impose delays as long as 18 months in ramping up production for preclinical studies and clinical trials.

In May, we wrote about ElevateBio, a company in Cambridge, Massachusetts offering full-scale facilities to develop cell and gene therapy products spun-off from academic research labs. ElevateBio is expected to have a central product development lab and manufacturing facility for gene and cell therapies to be shared among ElevateBio’s portfolio companies. The facility aims to provide automated protein engineering, virology, and immunology labs, as well as analytics and quality-control resources.

Both of these new enterprises are located in the biotechnology hotbed of Boston, but similar lab and manufacturing facilities will be needed throughout the country. A nationwide effort will likely require a combination of private and public investments, with federal money making up most of the public funds. One model to consider for these facilities are the national laboratories, part of the U.S. Department of Energy, but operated by private contractors.

The need for new drugs to treat infections is increasing, while current methods for finding and producing these drugs are disappearing. We need to start now, beginning with new precision-medicine processes to find those drugs, and new business models to get them in the hands of clinics.

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