New Insight for Antibacterial Drug Development

St. Jude Research Team Discovers a Triclosan-Resistant Enzyme in Pathogenic Bacteria

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In a paper published in the July 13 issue of the journal Nature, Richard Heath, Ph.D., and Charles O. Rock, Ph.D., researchers in the biochemistry department at St. Jude Children's Research Hospital(R), identify a new component in bacterial fatty acid synthesis, which presents resistance to triclosan, an antibacterial additive (commonly used) in many consumer products. This discovery has important implications for future antibacterial drug development and questions the widespread use of triclosan in consumer products.

Triclosan is the antibacterial agent included in a variety of household goods from soaps to cutting boards. Triclosan works by inhibiting an enzyme, called FabI, which is essential for fatty acid synthesis and bacterial survival. "Before now, FabI was thought to be ubiquitous and drugs that inhibit FabI would attack all bacteria," Rock said. But the research team found that the Streptococcus pneumonia, for example, has an alternative enzyme, which they dub FabK, that is unaffected by triclosan.

"The ability of bacteria to acquire genetic resistance to triclosan and related compounds through mutation illustrates that widespread use of this drug will lead to the appearance of resistant organisms that will compromise the usefulness of this class of drugs," Rock said. When resistance develops, it will also reduce the effectiveness of the antibacterial soaps and cleansers.

Rock reported in September 1998 that it was possible for E. coli bacteria to develop some resistance to triclosan by acquiring mutations in FabI. In a subsequent paper in April 1999, the team reported that the X-ray structure of triclosan bound to FabI confirmed that triclosan interferes with a specific biochemical process inside bacteria. The current study extends this work by showing that the substitution of FabK for the FabI gene in Escherichia coli confers complete resistance to triclosan. Triclosan has been touted as a non-specific agent that attacks bacterial membranes and kills randomly, but the present work shows that E. coli bacteria expressing the FabK gene are completely resistant to the drug.

"This finding is important because we now know that FabI-specific drugs will not be uniformly effective and that therapies will have to be specifically tailored for each bacteria according to the presence of FabI and/or FabK," Rock said.

Last year Rock reported that there is no compelling evidence that the inclusion of triclosan in consumer products offers increased protection against bacteria, and that the use of triclosan should be regulated. Recently, the American Medical Association has reached the same conclusion, adding more fuel to the spirited debate on the wisdom of using triclosan in soaps and other household products. "There is no strong rationale for the use of triclosan in these products, and it will lead to the emergence of resistance to triclosan and more importantly resistance to similar drugs that target FabI," Rock said.

St. Jude Children's Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital's work is supported through funds raised by the American Lebanese Syrian Associated Charities(R) (ALSAC)(R). All St. Jude patients are treated regardless of their inability to pay. ALSAC covers all costs of treatment beyond those reimbursed by third party insurers, and total costs for families who have no insurance.

Web site: St. Jude's Children Hospital

CONTACT: St. Jude's Children Hospital