By Janet Raloff
Often considered the single most important therapeutic discovery in the history of medicine, antibiotics are increasingly losing their punch. The more widely these wonder drugs are used, the greater the number of bacteria that evolve ways to elude the drugs’ lethality, creating a grave global health problem.
However, researchers at Wayne State University in Detroit have now developed a pair of novel strategies that may counter this dangerous trend. “Our goal is to design drugs that retain their potency in the face of increasing use,” explains team leader Shahriar Mobashery.
In one set of experiments, his group tackled the growing problem of antibiotic pollution. A person who takes an antibacterial drug excretes much of the dose intact (SN: 3/21/98, p. 187: https://www.sciencenews.org/sn_arc98/3_21_98/bob1.htm). Contaminating rivers or soil, the persistent drug kills many of the microbes it encounters but leaves behind those that can resist it (SN: 6/5/99, p. 356: https://www.sciencenews.org/sn_arc99/6_5_99/fob1.htm). Over time, Mobashery says, these surviving bacteria can transmit the resistance-conferring genetic material to both their progeny and neighboring bacteria.
To curb the build-up of such resistance, the scientists are designing antibiotics that self-destruct. A report of their first success is scheduled for publication in the Journal of Medicinal Chemistry. The scientists attached a light-sensitive component to a cephalosporin antibiotic chosen to represent important characteristics of this class of drugs. Within a few hours of exposure to the sun’s ultraviolet rays, Mobashery notes, the light-sensitive component falls off. What remains is unstable and quickly breaks apart into pieces having no antibiotic activity. “We consider this a proof of concept” that self-degrading drugs are possible, the bioorganic chemist says. Other versions of antibiotics on his drawing board include some that would break down at a specific acidity or after remaining wet for a certain period.
In a second series of experiments, Mobashery’s team created a derivative of the antibiotic kanamycin that evades bacterial resistance in a novel way. When kanamycin and related antibiotics enter a bacterial cell, often the bacterium produces an enzyme that inactivates the drug. It attaches a phosphate unit to a critical portion of the drug’s structure. The antibiotic that the Wayne State scientists designed accepts the phosphate unit, so the drug appears harmless to the bacteria. The new drug, however, soon shoves the phosphate off, uncloaking its lethality as it moves in for a kill. Bacteria using a phosphate-attaching enzyme as their tool for resisting drugs gain no survival advantage against such a novel drug, Mobashery observes. “A Star Trek fan, I view this [tactic] as similar to the way the Klingons cloak their ships,” he jokes. The bacterial enzyme unwittingly acts as a device that hides the enemy, he says”perhaps even encouraging the bacteria to take in more of the toxic drug than they ordinarily would. A paper describing the findings appears in the Dec. 22, 1999 Journal of the American Chemical Society.
Both strategies “are extremely clever,” says Richard Novick of New York University Medical Center. He says he’s particularly impressed with the cloaking. “I would never in a million years have guessed it would work,” he adds. However, he cautions that “bacteria are also pretty clever” and will eventually find alternate routes to resistance. He proposes that the new self-destruct feature would be most useful in limiting the environmental spread of new pharmaceuticals. For existing antibiotics, he fears, it’s probably “already too late-the cat’s out of the bag.”
