2013年12月18日 星期三

Antibiotics of the Future

As bacteria continue to develop resistance to existing antibiotics, scientists are working on new strategies to combat bug-borne infections and diseases, Shirley Wang reports. Photo: AP.
Scientists are working to develop new strategies to combat the growing threat of germs that current antibiotics can't fight.
Some researchers are testing new substances, such as silver, to combine with antibiotics to boost their killing power. Other researchers are making use of genetic sequencing of bacteria to help develop killer drugs at a faster pace than medical science was capable of in the past.
Another strategy aims to render harmful bacteria incapable of infecting people, rather than killing the germs outright. One such technique would neutralize disease-causing toxins by disrupting the bacteria's internal mechanisms.
Antibiotic resistance is a growing threat to public health, medical officials say. Common germs such as Escherichia coli, or E. coli, which can cause urinary tract and other infections, and Neisseria gonorrhoeae, which causes gonorrhea, are becoming harder to treat because they increasingly don't respond to antibiotics. Some two million people in the U.S. are infected each year by antibiotic-resistant bacteria and 23,000 die as a result, according to the Centers for Disease Control and Prevention. The CDC says it doesn't have historical numbers.
One of the biggest threats is from Enterobacteriaceae, a family of germs that naturally lives in the gut and includes E. coli, the CDC says. There are about 9,000 cases a year of infections from the germs that can't be treated with usual antibiotics, resulting in 610 deaths. In 1998, there was just one case. Patients who don't respond to normal antibiotics are given older drugs that had been discontinued because of severe side effects, such as kidney damage, the CDC says.
Scientists say that Enterobacteriaceae are particularly hard to kill because of an outer cell wall that prevents many antibiotics from penetrating. James J. Collins, a professor of biomedical engineering at Boston University and Harvard University, and his colleagues recently discovered that adding trace amounts of silver—long known to have antimicrobial properties—allows the common antibiotic vancomycin to work against E. coli, whereas the antibiotic isn't effective against the microbe on its own. The silver appears to make the outer walls of the bacteria more permeable, allowing the antibiotic to get in and do its job, says Dr. Collins, who published the findings in the journal Science Translational Medicine in June.
Some pharmaceutical companies are experimenting with other types of additives with the aim of short-circuiting bacteria's defenses.
Researchers at Merck & Co., in Whitehouse Station, N.J., are targeting an enzyme called beta-lactamase that lives in certain bacteria and neutralizes antibiotics sent to destroy them. By adding an enzyme-inhibiting agent called MK-7655 to the antibiotic imipenem, researchers managed to kill about 97% of a type of antibiotic-resistant bacteria that causes urinary-tract infections and pneumonia, according to Nicholas Kartsonis, head of clinical development of antibacterial, antifungals and non-hepatology viruses at Merck Research Labs.
Synthetic Biologics Inc. is taking advantage of beta-lactamase's ability to neutralize antibiotics by adding a modified version of the enzyme to the drugs. The aim is to prompt the antibiotic to break down when it reaches the bowel, where side effects and drug resistance for bacteria called Clostridium difficile, or C. difficile, develops, but to leave the antibiotic intact in the bloodstream. The process should allow larger doses of antibiotics to be administered without the patient suffering typical side effects such as gastrointestinal problems, says John Monahan, who heads research and development for the Rockville, Md.-based company.
C. difficile, which causes life-threatening diarrhea and is blamed for 14,000 deaths a year, can spread rapidly in hospital patients on antibiotics. Although there are drugs to treat C. difficile, the bacteria are resistant to many antibiotics used to treat other types of infections.
Antibiotics naturally lose their effectiveness over time as bacteria populations build up resistance, and new drugs need to be continually developed to take their place. But antibiotic development by pharmaceutical companies slowed sharply after about 1990, in part because they are less profitable than other drugs used to treat chronic diseases. Compounding the problem has been an overuse of antibiotics in people and farm animals, which has accelerated the creation of antibiotic-resistant germs.
"Antibiotics have a finite lifetime because resistance is inevitable," says Michael Fischbach, a bioengineering and therapeutic sciences professor at the University of California, San Francisco. "Therefore, there's always a need to innovate."
Bacteria have ways of defending themselves against other bacteria, and most antibiotics are derived from the toxins they use. Identifying and developing new antibiotics is a long and slow process. Now, scientists are able to more efficiently scrutinize microbes for undiscovered antibiotics by sequencing their genomes and then using computer analysis to look for gene patterns that suggest a new antibiotic recipe. Typically, antibiotics are encoded by anywhere from 10 to 40 genes.
Sean Brady, head of the Laboratory of Genetically Encoded Small Molecules at Rockefeller University in New York, and his colleagues recently zeroed in on half a dozen gene sequences. The team found that the genes were encoded for toxins that appeared in lab testing to be active against pathogens resistant to the antibiotic vancomycin, which is commonly used to treat infections in the gut. The research was published in the Proceedings of the National Academy of Science in June.

2 million

The number of U.S. patients per year whose infections aren't treatable with the existing array of antibiotics
Whether the antibiotic will be useful in treating people remains to be seen, says Dr. Brady. The main problem with identifying new antibiotics isn't that they don't work, but that they cause severe side effects or toxicity, drug makers say.
Another group of researchers, headed by Dr. Fischbach at the University of California, has found a handful of new antibiotics that kill methicillin-resistant Staphylococcus aureus, or MRSA, by sequencing genomes of bacteria found in the environment. MRSA can cause a range of illnesses from skin infections to pneumonia and bloodstream infections.
An unusual strategy doesn't aim to kill bacteria at all, but rather to make them less harmful. Since bacteria only cause infections when their population has reached a certain threshold, called a quorum, researchers are looking for ways to disrupt the chemical signals the bugs use to communicate with each other. Another approach aims to neutralize toxins or disrupt other signaling molecules that are necessary for bacteria to be infectious.
"We don't challenge them to a duel but basically confuse them into not causing infection," says Gerry Wright, a professor of biochemistry and biomedical sciences at McMaster University in Hamilton, Ontario.
Dr. Brady and his team at Rockefeller University demonstrated that disrupting a cluster of genes reduced the virulence of a microbe that causes infection affecting the lungs, bones and joints. The researchers published the work late last year in the Journal of the American Chemical Society.