Now researchers have come up with a possible substitute that utilizes the metal gallium to mimic iron needed by bacteria need to survive. Rather than a drug designed to attack the bacteria itself, gallium boosts of the body's own natural defenses by fooling bacteria into thinking they are well-nourished.
"This approach might intensify a stress already imposed on a bacteria by host defenses," says study co-author Pradeep Singh, assistant professor of medicine and microbiology at the University of Washington School of Medicine. "The immune system has got the bacteria in an armlock and the belly's exposed, and we try to give it a sucker punch in the kidney."
The new approach, described in the April 2 issue of the Journal of Clinical Investigation, takes advantage of bacteria's dependence on iron, which is a constituent of many of their essential enzymes. Iron is also necessary for bacteria to form biofilms, clusters of cells that adhere to surrounding tissue. Once the body detects a bacterial invader, the immune system gobbles up free iron and locks up any stores of the element.
That is where gallium comes in. Despite the element's position five spots from iron on the periodic table, many biological systems are unable to distinguish it from an iron ion. Singh, using methodology co-developed with study co-author Bradley Britigan of the University of Cincinnati, tested bacterial suspensions both in vitro and in mouse models to see if iron-starved bacteria would feel sated in the presence of the beguilingly similar element.
The team observed that small concentrations of gallium—mixed with nitric acid to become gallium nitrate in test tubes—could inhibit the growth of Pseudomonas aeruginosa, an antibiotic-resistant pathogen that commonly infects the impaired lungs of patients with cystic fibrosis (an incurable disease in which there is a mucus buildup in the lungs and pancreas; over half of the disorder's sufferers do not make it to age 18). Higher concentrations of the metal destroyed the bacteria at dosages less potent than those approved by the FDA to intravenously reduce excess calcium in the blood. When subject mice inhaled a gallium solution, the element countered acute, typically fatal amounts of P. aeruginosa. To mimic this Trojan horse's effectiveness against chronic exposure to the bacteria, the metal was pitted against a biofilm (which over time allows the bacteria to acquire a resistance 1,000 times stronger than as free-flowing cells, according to Singh) in the mouse's lungs. The new treatment reduced bacterial counts 1,000-fold.
Singh and his colleagues analyzed the genes in the bacterial cell to determine which ones were vulnerable to the gallium solution. The gallium apparently causes "everything to go haywire in the iron sensing of the bacteria," Singh says, noting that the genetic profile seemed to indicate a particular cell was simultaneously iron-starved and iron-replete.
Despite the resounding success of both the test tube and mouse studies, however, Singh stressed that gallium has yet to go through human clinical trials. But he says that he is optimistic about the gallium's potential, especially as a treatment for cystic fibrosis, which currently has no cure. The goal, he says, is "to have patients inhale gallium and achieve higher concentrations in the lungs and lower concentrations in the rest of the body," because gallium nitrate has been found to impair kidney function.
Unfortunately, he says it is iffy whether gallium could prevent bacteria from mutating into forms that would resist it. "Like any antimicrobial agent," he concedes, "there is the probability that resistance would grow over time."