DRUG COMBO KILLS RESISTANT TB MICROBIOLOGY: Inhibitor and antibiotic work together against tuberculosis Meropenem (gray) binds in the active site of the TB β-lactamase BlaC.
A
COMBINATION of two commercially available drugs is effective against extensively drugresistant (XDR) Mycobacterium tuberculosis, lab tests show (Science 2009, 323, 1215). XDR strains are resistant to all the drugs typically used to treat TB. Biochemist John S. Blanchard of Albert Einstein College of Medicine at Yeshiva University, in New York City, and coworkers tested the drugs meropenem, a β-lactam antibiotic, and clavulanate, a β-lactamase inhibitor. β-Lactam antibiotics have not found use as TB drugs because mycobacterial β-lactamase enzymes normally hydrolyze them before they can reach their target. Blanchard’s lab had previously shown that clavulanate is an irreversible inhibitor of the β-lactamase produced by M. tuberculosis, an enzyme called BlaC. The researchers combined meropenem with clavulanate because BlaC hydrolyzes meropenem very slowly. The combination inhibited 13 XDR TB strains, as
EPA MUST RETHINK AIR STANDARD POLLUTION: Agency failed to explain why particulates limit protects health, court says
Fine particulate pollution, a by-product of combustion, is found in smoke and haze.
SHU T TERSTOCK
T
HE ENVIRONMENTAL Protection Agency has
an opportunity to make the national air quality standard for fine particulate matter more protective because of a federal appeals court ruling on Feb. 24. In its decision, the U.S. Court of Appeals for the District of Columbia Circuit instructed EPA to reconsider the Bush Administration’s 2006 decision to maintain, and not tighten, the 1997 standard for fine particulates. That annual standard is 15 µg of fine particulate matter per cubic meter of air. Exposure to fine particulate matter, defined as particles with a diameter of 2.5 µm or smaller, is linked to cardiovascular problems and premature death. Sources of fine particulates include power plants, industrial processes, vehicle exhaust, and forest fires. EPA set the 15 µg/m3 standard in 1997 and reviewed W W W.C EN - O NL I NE .ORG
12
well as organisms in a nonreplicative “persistent” state. This state is usually not susceptible to antibiotics and represents the largest reservoir of the mycobacterium in humans. Blanchard speculates that the clavulanate-meropenem pair is so effective because meropenem itself also inhibits BlaC. “Meropenem, by being able to bind to and inhibit the β-lactamase, commits suicide so the rest of the meropenem molecules can go find their targets,” he says. The observed effect “may stimulate further drug development research into capturing the β-lactam class of antibiotics for use as anti-TB agents,” says William Bishai, codirector of the Center for Tuberculosis Research at Johns Hopkins School of Medicine. One of the stumbling blocks in developing the drug combination for use in patients is figuring out the pharmacokinetics, says Clifton E. Barry III, head of the TB research section at the National Institutes of Health and Blanchard’s collaborator. “You want to be able to give the β-lactamase inhibitor and the β-lactam in a way that maximizes the lifetime of the β-lactam,” he says. Blanchard and his team hope their results will overturn long-held beliefs about β-lactams. “I’ve been told that β-lactams are not effective against TB, and we’re wasting our time trying them,” Blanchard says. “When you run up to paradigms and suggest that the paradigms may not exactly be true, you run into a lot of skepticism.”—CELIA ARNAUD
it in 2006, as required by the Clean Air Act. During the review, EPA’s Clean Air Scientific Advisory Committee recommended lowering the fine particulate standard to between 13 and 14 µg/m3 to protect health, on the basis of studies conducted since 1997. In September 2006, EPA’s then-administrator, Stephen L. Johnson, a Bush appointee, chose not to heed the recommendation of the science advisers and decided to maintain the 15 µg/m3 standard. The court faulted EPA for not describing how the 15 µg/m3 standard would be protective of health. “EPA failed adequately to explain why, in view of the risks posed by short-term exposures and the evidence of morbidity resulting from long-term exposures, its annual standard is sufficient to protect the public health,” the court said. The court returned the standard to the agency for reconsideration, providing the Obama Administration with an opportunity to tighten it. Environmental activists and 16 states challenged the 15 µg/m3 standard in court, saying it was not protective. Paul Cort, an attorney with the nonprofit environmental law firm Earthjustice, called the decision a “victory for anyone who breathes.” Attorneys representing electric utilities and the American Chemistry Council, a trade association, did not respond to requests for comment.—CHERYL HOGUE
MARC H 2 , 20 09
© 20 09 SCIE NCE
NEWS O F TH E W E E K
