Start-up Profiles

Nature Biotechnology  20,  BE17-BE18 (June 2002)

Microbia

Exploiting microbial circuitry to fight infection

Staphylococcus aureus biofilms after 4 days of growth on a catheter implanted into a mouse.

Each year, millions of people fall foul of serious bacterial and fungal infections, many of which are resistant to existing therapies. At least part of the problem can be attributed to bacteria forming thin films, "biofilms", which are involved in an estimated 65% of human bacterial infections and which are extremely difficult to eradicate. To address this issue, Microbia is focusing on finding means to clear biofilms and fungal infections, as well as to enhance the production of microbially produced drugs and fine chemicals. (Click here for company profile.)

Biofilms—communities of complex, highly differentiated bacteria encased in an extracellular matrix—result when free-floating bacteria adhere to surfaces such as catheters, prosthetic implants, internal organs, teeth, and, in industrial settings, food processing equipment and water filters. Bacteria undergo physiological changes that allow them to attach to each other and the surface, and the bacteria in biofilms may produce proteins that differ from those of "planktonic" bacteria by up to 40%. Existing antibiotics may kill free-floating bacteria released by biofilms and reverse the associated symptoms of the infection, but they do not get rid of the biofilms.

In the past, screening for new anti-microbials has been limited primarily to searching for compounds that could kill or prevent the growth of the relevant organism. With drug resistance on the rise, more potent anti-infective drugs with novel modes of action have been sorely needed. Microbia's technology is based on proprietary knowledge of the regulatory mechanisms that microbes use to sense and respond to changes in their environment. Physiological adaptation to changes in temperature, moisture, availability of an attachable surface, availability of nutrients, pH level, the presence of competitors, etc., can result in the creation of bacterial biofilms 1,000-fold more resistant to existing antibiotics than free-floating bacteria.

Part of Microbia's drug discovery program is focused on drawing up master wiring diagrams of the bacterial circuits controlling biofilm formation, dissolution, and mechanisms of biofilm resistance. The company has in-licensed a variety of high-throughput genetic screening technologies to identify novel compounds that target biofilm formation and resistance. So far, the lead molecules in its Anti-Biofilm product line are in the optimization stage, with the ultimate goal of bringing Microbia-branded products to market.

Another target are disease-causing fungi. Beacause fungal and human cells are similar, it is difficult to identify inhibitors of fungi that do not harm human cells. Microbia uses proprietary, highly multiplexed cell-based screens and wiring diagrams of fungal regulatory systems to develop drugs that target those systems to block the ability of fungi to cause disease. Because these targets are specific to fungi, drugs directed at them have the potential to be well tolerated in humans. Additionally, Microbia has developed a toolkit of hundreds of sensing/adapting system "regulators" and is commercializing it via service contracts to companies making fungally derived drugs as well as fine chemicals. One such chemical, citric acid, has a market of $1.5 billion/year. By helping to develop new fungal strains with improved product yields, Microbia hopes to generate significant near-term revenue until its drug discovery programs generate validated leads.

Microbia's patent portfolio includes applications covering the discovery of novel anti-infectives and novel biofilm inhibitors, and methods and reagents useful for improving fungally derived drug production. The company has also exclusively licensed several inventions from the Whitehead Institute (Cambridge, MA) covering the regulation of fungal gene expression, novel transcription factors, and selective control of microorganisms, and from Harvard Medical School (Boston, MA) covering the "logic circuits" of bacterial biofilm formation. MF