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Columns: August 01, 2017 (Vol. 37, No. 14)

TIME for Parallelized Drug Discovery

Bactevo Speeds Discovery with Multichannel Chemistry and Microdroplet-Based Screening

  • Bactevo’s Totally Integrated Medicines Engine (TIME) assays 100 million samples per hour. Running multiple assays in parallel, it harnesses next-generation synthetic bio-space libraries, identifies disease networks, and targets and deploys chem- and bioinformatics for knowledge mapping to create and advance in vivo-ready therapeutics while simultaneously performing ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) lead profiling.

    In essence, TIME combines library generation, candidate screening, and assay analysis to support a high-throughput approach to drug discovery. TIME can perform a battery of assays in weeks that otherwise would take years to complete, says David Williams, Ph.D., Bactevo’s CEO. In his estimation, TIME could shorten drug-development times by orders of magnitude.

    Dr. Williams suggests that in terms of the depth and quantity of information produced, TIME is the Google of drug discovery. “It will radically increase the success rate and speed of medicine discovery by harnessing an unprecedented depth of relevant phenotype and profiling data simultaneously,” he adds. “We believe it will revolutionize the industry.”

    The key benefit is the ability to select molecules more rationally. TIME generates a tremendous amount of data on safety and efficacy during the earliest stage of lead selection. As a consequence, explains Dr. Williams, users can be more sure of the molecules they put into the clinic.

    “Also, users can perform the initial high-throughput screening on patient-derived cells or tissue, thus making a critical link with the disease,” he notes. “This can change the whole paradigm of safety and efficacy during drug development.”

  • Natural and Synthetic Libraries

    Bactevo developed TIME by mining the natural products of bacteria to engineer product libraries that reflect the huge diversity of chemical structures that are synthesized by organisms across the bacterial kingdom. Using naturally occurring microbial products as a starting point increases the chances that any resulting drug candidates will have biological relevance and, thus, possess the potential to interact with mammalian systems.

    The TIME platform was then extended to include the capability to create totally synthetic chemical libraries, with built-in medicinal properties. The synthetic libraries are generated as required and screened with multiple replicates and at different concentrations, allowing both positive and negative data to be used to generate what Bactevo calls “Total Structure Activity Relationships.” That, in turn, provides the foundation for hit selection and chemical optimization.

    To perform the assays, TIME uses two approaches. The first synthesizes and screens billions of tagless molecules at up to millimolar concentrations within days. The second, complementary to the first, identifies and isolates biologically evolved small molecules. The resulting synthetic chemical library also can be inspired by hits obtained from the engineered bacteria, thus allowing the biologically evolved chemical scaffolds to be further “evolved” to ideal drug candidates.

  • Initial Focus: Mitochondrial Disease

    Bactevo is using TIME internally to develop its lead programs in mitochondrial disease. “The mitochondria is a major gatekeeper for other diseases,” Dr. Williams points out.

    The program is designed to develop therapeutics to improve mitochondrial biogenesis to address defects in mitochondrial function that result in the rare, progressive mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome and Leber hereditary optic neuropathy (LHON). Diseases of the central nervous system, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), are included in the scope of work. To advance this work, the company also is collaborating with researchers at the Wellcome Trust Centre for Mitochondrial Research, a leading center for basic mitochondrial disease research and patient care.

    “We’re doing a huge number of things simultaneously,” Dr. Williams says. For example, in addition to its mitochondrial program, Bactevo is in the early stages of research to generate new antibiotic drugs that combat the highly drug-resistant Gram-negative pathogens that cause septicemia, and chest and severe urinary tract infections. The antibiotic program is funded, in part, by the $2.0 (£1.5)-million grant it received when it won Innovate UK’s Innovate Award in January 2017. The company also is expanding the number and types of reagents that can be used with TIME to increase its therapeutic reach and chemical diversity.

    Nearer-term, the company intends to demonstrate the platform in a number of different areas. “Two years from now,” predicts Dr. Williams, “we expect to have products ready to transition to clinical development.” 

  • Evolution and Collaboration

    Bactevo operated in stealth mode until this spring and only recently began talking about TIME. Now, the company is in discussions with select pharmaceutical companies with an eye toward participating in collaborative discovery programs and ultimately presenting its partners with compounds based upon exacting requirements. “We’re evolving a business model that keeps the value of the technology in the company,” insists Dr. Williams. At the same time, Bactevo is augmenting capabilities through collaborations. Later, Dr. Williams says, the company may consider licensing TIME for applications beyond pharmaceuticals.

    “Usually, I see limitations with technologies,” remarks Dr. Williams. “I don’t [see them] here.” 

    Pharma seems to agree with this sentiment. In his talks with Big Pharma about TIME, Dr. Williams keeps hearing the same question: “How is it that you’ve done this and we haven’t?” The answer that Dr. Williams proposes is this: “In a small company, unless you solve a problem rapidly, you don’t survive long.”

    This imperative to succeed permeates Bactevo, which addresses existential threats by cultivating its staff’s problem-solving skills. “We have an unusual mix of outstanding scientists and disciplines from five nationalities working within 10 yards of one another and talking about their work,” informs Dr. Williams. The mix includes experts in microfluidics, sequencing, nanofabrication, artificial intelligence, and other disciplines working together to solve problems. It also helps, states Dr. Williams, that Bactevo is based in Cambridge, U.K., “a world-leading hot-bed of innovation in many different disciplines.”

  • Bactevo

    Location: The Merrifield Centre, Rosemary Lane, Cambridge, U.K. CB1 3LQ

    Phone: +44 1223 423506

    Website: www.bactevo.com

    Principal: David Williams, Ph.D.

    Number of Employees: 15

    Focus: Bactevo has developed a Totally Integrated Medicines Engine (TIME) that performs 100 million assays per hour. TIME is being used to rapidly advance the speed, efficiency, and quality of drug discovery programs internally and with pharmaceutical partners.