New findings on the role of the commensal microbiota in establishing a robust immune system suggest that this complex ecosystem which every human carries from shortly after birth is of paramount importance to maintaining effective immune surveillance essential to preventing the development of cancers. Antibiotics and many other drugs can profoundly disturb this ancient ecosystem and the immune system with the result that serious infections with otherwise benign microorganisms are usually the proximate cause of death for victims of cancer and other "major killer" diseases. The increasing resistance to conventional anti-bacterial agents not only in pathogens, but especially in the commensal bacteria is an ominous challenge to our ability to prolong the patient's life sufficiently to allow agents directed at the underlying disease to be effective. In addition, understanding the metabolic capacity of this ecosystem will be essential in the development of new drugs. It is already well established that commensal microbes pre-metabolize and co-metabolize many therapeutic agents. Since such studies are almost exclusively done in animal model systems, there is minimal understanding of the impact of microbial processing on the efficacy and side effects of drugs administered to humans. The work of my laboratory directly addresses these issues: the the molecular characterization of commensal flora of the gut and the persistence and spread of antibiotic resistance.

2. Employing bacterial proteins to prevent Hg intoxication

Humans in both developing world susbsistence cultures and also in the most developed world are burden by Hg intoxication in two very different ways, each of which is addressed by our work. Increasing contamination of both freshwater and marine fish by the potent neurotoxin methylmercury has led interdiction of fishing in many areas, thus limiting one of the major sources of animal protein for non-industrialized and/or economically disadvantage populations world-wide. In the developed world, the use of Hg in dental restorations ("amalgams") exposes 80% of most North American and European populations to ingestion of ca. 12 micrograms of inorganic Hg per day. Owing to the pleiotropic nature of Hg pathologies, pinpointing any single disease which might be caused by such exposure has been very controversial. However, it is universally agreed that inorganic Hg is toxic and no lower limit for its deleterious effect has ever been established. Moreover, there is increasing evidence that inorganic Hg can be converted to methylmercury by certain commensal microbes within the human host.

One of the bacterial enzymes on which we work, the organomercurial lyase, evolved in Hg-exposed bacteria specifically to degrade such compounds as methyl mercury. We are currently engaged in structure-function analysis of the organomercurial lyase with the aim of enhancing its activity and adapting it to commercial application for detoxification of fish products as well as for detoxification of humans exposed to methylHg. We have also re-engineered the highly sensitive and specific Hg-binding domain of the metalloregulatory protein, MerR, to function as a robust, stand-alone, metal sequestering agent and/or as a specific biosensor for Hg. This work is covered in a US patent application filed in October 2000.