Scientists have been digging deep in the dirt microbiome for decades in search of potential new drug compounds, successfully developing cholesterol-lowering medications, immunosuppressants and other disease-fighting medications. Soil continues to be a rich source of new organisms, as bacteria and fungi compete for resources and utilise a variety of chemical compounds.
Despite the huge potential of soil, new antibacterial natural-product discovery has decreased dramatically in the past few years says David Pompliano, Lodo Therapeutics’ co-founder and chief scientific officer.
“Although there have been discoveries of new antibacterial natural products including platensimycin, kibdelomycin and teixobactinin, they have not had the safety and pharmaceutical properties to be approved as a marketed medicine,” he explains.
This was a contributing factor in big pharma drastically reducing investment in natural product discovery at the end of the 1990s.
“The groups within pharma were discovering the same molecules – penicillins, tetracyclines and macrolides – over and over again using the same discovery methods, namely laboratory growth of bacteria and fungi isolated from environmental samples,” he continues. “This was costly and time-consuming, and it made no sense to continue. Lodo’s metagenomic approach overcomes the ‘culturing’ problem and allows us to access the entire biosynthetic potential of the bacterial microbiome.”
Breaking new ground: extracting DNA code directly from soil
A major breakthrough earlier in 2018 demonstrated the power of this new soil sampling technology. Rather than take the traditional (and largely unreliable) petri-dish approach to growing bacteria, Professor Sean Brady’s laboratory team at Rockefeller University, New York, were able to extract DNA encoding the synthesis of secondary metabolites directly from different soil organisms.
Expressing one of these gene clusters resulted in the discovery of malacidin, a chemical that is able to fight the hospital superbug MRSA and appears to be non-toxic to humans. It is hoped that malacidin can be developed into a new treatment that can be used on a global scale.
This new technology has the potential to revolutionise the way scientists harness the microbiome and big pharma are keen to industrialise the process. The recent collaboration between Lodo Therapeutics Corporation and pharma giant Genentech demonstrates a high-level of confidence in the technology, with Lodo eligible to receive up to $969m in upfront fees and milestone payments.
Lodo and Genentech: a natural partnership to transform drug discovery
Lodo is a drug discovery and development company focused on identifying and producing novel,
bioactive therapeutics directly from the microbial DNA sequence information contained in soil and other natural environments. It has received support from a consortium of big pharma venture funds, as well as the Bill and Melinda Gates Foundation. The organisation was formed in 2016 by Accelerator Life Science Partners specifically to pursue Brady’s scientific vision and has its headquarters in New York City.
“Lodo is a leader in the microbial metagenomic space as it applies to drug discovery,” says Pompliano, “so we are a natural fit with Genentech which has a very strong interest in exploring novel technologies and building their natural products base. Both companies are very scientifically driven so the attraction was mutual.”
Genentech, part of the Roche group, has a proven track record in bringing multiple therapeutics to the global market to treat patients with serious and life-threatening medical conditions.
Mark Rowen, director of drug technologies business development at Genentech, believes the partnership with Lodo has the potential to radically transform drug discovery and the way industry thinks about developing medicines.
“In our partnership with Lodo we are accessing innovative technologies to discover medicines for particularly challenging drug targets,” he explains. “As Lodo’s first biopharma partner, we will be pioneering the science in this space and potentially unlocking new ways to treat serious diseases and shape the future of medicine. Genentech will utilise Lodo’s proprietary genome-mining and biosynthetic gene-cluster assembly platform to identify novel molecules with therapeutic potential against disease-related targets of interest, ranging from infectious diseases to cancer.”
Traditionally, scientists had to culture the actual bacteria from an environmental sample – be it soil, sea water or another natural environment – in order to isolate the molecules they produce which, says Pompliano, harnesses very little of the sample’s true potential since only a tiny fraction of environmental bacteria are easily cultured in the laboratory.
“The process of putting that sample on petri dishes and trying to grow fungi or bacteria is a very highly selective event,” he comments. “Instead we go straight to the source of the molecular blueprint for making natural products. We extract DNA directly from these environmental samples.”
Digging deep for high investment
It is this break with traditional methods that has big pharma companies eager to invest.
“We are mining the microbes that can’t be grown in labs using the power of next-generation sequencing, bioinformatics and genetic engineering,” says Rowen. “Whereas traditional approaches have only enabled researchers to access the 1% of organisms that could be grown in a lab, Lodo’s technology has the potential to unlock the other 99%.”
With this level of access to the microbiome, the appeal for big pharma is obvious and further billion-dollar investment deals are likely as the technology progresses.
“What that means in a practical sense,” continues Pompliano, “is that we can access the full 100% of biosynthetic capability that is present in bacterial microbiome. That’s what our partners and potential partners place high value on. Sean Brady’s lab has isolated a number of molecules using this approach and we felt it was time to make it more directly applicable and bring the power of investment to industrialise the process.”
Rowen is reticent about offering specifics on Genentech’s objectives, but believes it will enable the company to develop transformative medicines in completely new ways, and to discover novel molecules with activity against historically intractable disease targets.
“The Lodo approach offers significant advantages and although we’re not disclosing details about targets, we may elect to expand the collaboration in the future. We are not limited by disease area.”
Lodo is also cautious about future developments, but it is clear that the technology has the potential to be a game-changer for the industry.
“We would be very happy if we could identify biosynthetic clusters in any type of environmental sample and rapidly produce the molecules that are encoded by them,” Pompliano concludes. “There are hurdles to making this a really super-efficient method, which is partly why our company was founded to work on the industrialisation of the process. Our ultimate goal is to leverage the full biosynthetic capability of nature to produce a steady stream of medicines that treat diseases of unmet need – 100% of the bacterial microbiome instead of just 1%.”