Scientists may have new tool in bacteria fight

Methicillin-resistant Staphylococcus aureus bacteria is commonly known as MRSA and is a major source of infections in hospitals. (CDC) -

By Scott LaFee
Union-Tribune Staff Writer
August 28, 2009

For years, scientists and doctors have watched with frustration as their arsenal of antibiotics has been reduced by the growing and inevitable emergence of drug-resistant bacteria and other microbes.

What they have needed, what modern medicine requires, is a new way to attack and kill infectious, disease-causing pathogens such as tuberculosis and multidrug-resistant staphylococcus.

In a paper published today in the journal Chemistry & Biology, researchers at Burnham Institute for Medical Research in La Jolla, with colleagues at the University of Texas Southwestern Medical Center and the University of Maryland, say they may have found the basis for a new class of antibacterial agents capable of overcoming current multidrug resistance.

“The importance of emerging antibiotic-resistant pathogens cannot be overstated,” said Dr. Victor Nizet, who studies human immunology and infectious disease at the University of California San Diego. “There's no drug currently in clinical medicine in which there isn't at least one resistant strain of pathological microbe.”

Andrei Osterman, an associate professor at Burnham and member of its Infectious and Inflammatory Disease Center, said the new findings were not a silver bullet. “What we've found is a golden target,” he said.

That target is a bacterial enzyme called NadD, or nicotinate mononucleotide adenylyltransferase. If the enzyme is absent or its activity is suppressed, the bacterium dies. Versions of NadD are found in almost all cells, including human.

Using computer modeling, the researchers matched more than a million chemical compounds against the enzyme, eventually identifying a handful that interacted with and inhibited NadD activity. Subsequent experiments using E. coli and anthrax bacteria confirmed the compounds' inhibitory potential. But the compounds do not affect the human version of the NadD enzyme because its molecular structure is different.

“We're a long way yet from having an actual, new class of antibiotics, something that microbial pathogens have not seen before,” Osterman said. “But this is a major step. It is proof of concept. We've proved that this enzyme is a good target and that by suppressing it, you can kill bacteria.”
Osterman said it will require several more years of testing and research before any new, NadD-based antibiotic might emerge. The newly identified compounds must be further refined and improved, tested for toxicity and effectiveness in animal models and, eventually, in humans.
The bulk of that research will likely occur in academic and institutional settings, not within the pharmaceutical industry, which broadly views antibiotic research as less lucrative than other endeavors. Osterman's research was funded by a grant from the National Institute of Allergy and Infectious Diseases.

Development of a new and effective broad-spectrum antibiotic can't come soon enough. Antibiotic resistance has become a major medical issue, with some pathogens having evolved through random mutations and the misuse of antibiotics to become almost invulnerable to the one-time “wonder drugs.”

Indeed, more than half of all Staphylococcus aureus infections in U.S. hospitals, where it is a persistent scourge – are resistant to formerly potent antibiotics such as penicillin, methicillin, tetracycline and erythromycin, according to the Centers for Disease Control and Prevention. In such cases, only the strongest, newest antibiotics, such as vancomycin, work – and some bacterial strains are now resistant to it.

For a variety of reasons, most pharmaceutical research has tended to focus on tweaking existing drugs to keep them effective or relevant, said UCSD's Nizet, who is also on Burnham's scientific advisory board. But that's clearly not enough.
New chemicals with antibiotic properties must be found – new chinks in microbial armor revealed.

“This research is an example of the latter,” Nizet said. “It's one of a handful of approaches that all have to be pursued in combination because things aren't going to get better anytime soon. Bacteria is perfect proof of evolution in action, constantly adapting to selective life-and-death pressures. These pathogens are not going to go away.”

Row over South African athlete highlights ambiguities of gender

By Thomas H. Maugh II
Los Angeles Times
August 21, 2009

Some have raised doubts whether Caster Semenya is a woman. But a scientist says physical features do not always match DNA or hormones. A variety of genetic and hormonal anomalies can lead to ambiguity.

Despite what one might think, it is not always easy to tell who is male and who is female.

In sporting events, officials who watch athletes produce a urine specimen usually can see immediately whether their genitals match their proclaimed sex. But that analysis can leave room for doubt, as with South African runner Caster Semenya.
The problem, said Dr. Joe Leigh Simpson, a pediatric geneticist at Florida International University, is that genetic or hormonal abnormalities can affect any organ system "and the gonads and external genitalia are not exempt from that." When such anomalies do occur, "it can produce confusion" because hormone levels and other aspects of physiology may not match appearance.

Moreover, there is "no single process" for determining sex because every case is different, he added. For years, sports authorities considered only the sex chromosomes: If they are XX, the athlete is female, XY and he is male. Technicians would swab the athlete's mouth to remove some cells, look at the sex chromosomes and make a determination.

But at the 1996 Atlanta Olympics, eight female athletes were determined to have XY chromosomes and were booted from the Games. Further studies, however, showed that they were physiologically female even though their genes said they were male, and they were reinstated.

Genes are only a blueprint, and sometimes nature doesn't follow the blueprint precisely. Take the examples of XY athletes who appear to be women. At least five enzymes are required to synthesize testosterone, the hormone that produces most male characteristics, and occasionally one of those enzymes is defective. When that happens, the genitals are typically male and tiny, the person doesn't have much body hair and he is generally feminized. By determining which testosterone precursor is present in unusually large amounts, researchers can determine which enzyme is defective. Such people are normally eligible to compete as women.

In other genetic males, the receptor that the testosterone binds to is defective and it doesn't matter how much testosterone is present. That male is classified as androgen resistant, but the results are the same: feminization. Genitalia are typically female. Often, such people are raised as females and don't find out they are genetically male until they don't get menstrual periods. They are often tall, slender and attractive, and there has been speculation that movie stars Marlene Dietrich and Greta Garbo were in this category.

Neither anomaly gives the person strength or endurance beyond that of a normal female and subjects are allowed to compete as women.

The condition of being genetically female, or XX, but appearing male can often be traced to congenital adrenal hyperplasia, in which the adrenal glands produce excess testosterone. The woman may look like a boy with tiny male genitals, but once a month will pass blood. If the condition is caught early in life, doctors usually recommend surgery to create female genitalia. But many persons with the condition live normal lives as men.

Another possibility that could account for a disconnect between genetics and appearance is mosaicism, in which the individual has more than one set of genes, in some cases, some cells could be XX and others XY. That occurs because of a faulty division at a very early stage in the embryo, or if two embryos fuse, and can produce a variety of mixed sexual signals.

The genetics community has "well-oiled machinery" to detect and deal with sexual abnormalities in newborns, Simpson said. But when it comes to adults, the process may end up being little more than a judgment call. The ultimate determinate in sporting events: Does the abnormality give an unusual benefit?