Philip Domenico, PhD, says not only MRSA but also tuberculosis, infections on wine grapes, rust on ship bottoms, and many other banes of human existence are vulnerable to the action of bismuth-thiols (BTs), which contain the active ingredients in Pepto-Bismol, tweaked to be much more potent, and to allow them to breach the slime that many bacteria use for defense. BTs are currently in Phase I clinical trials for topical use, and the U.S. Army is studying their application for serious wound healing on the battlefield.
Regarding the slime-producing bacteria, Domenico says, “These guys have been around for billions of years, and they’ve figured out a lot of things. They put out long sticky strands of complex carbohydrates, polysaccharides.” The strands stick together and enable masses of cells to stick to objects in a slimy coating called biofilm. The slime also camouflages cells, protecting them from predators, antibodies, and antibiotics.
Biofilm is a good thing to have on a rock, Domenico explains, since it helps break down the nutritive minerals in the rock, contributing to the building of soil and growth of plants. Biofilm on our teeth — known as plaque — is more problematic. If we’re not healthy, the bacteria can eat away at gums and teeth.
“The digestive tract is basically a long tube of slime,” he says. “There are hundreds of trillions of bacteria in the gut, and every so often, they get unbalanced, and toxic substances are produced. One way to address that is to get the right probiotics into the system,” so the healthy bacteria outweigh the unhealthy ones. Another way is to take Pepto-Bismol, which mitigates the buildup of slime through the action of bismuth subsalicylate, a combination of bismuth and aspirin.
“Bismuth is an element with the atomic number 83, one higher than lead,” explains Domenico, taking out a periodic table and pointing to the column with the letters “Bi” highlighted. “You can see it’s in the same family as arsenic and antimony. They are metabolic poisons that interfere with iron metabolism and energy production. This is why it stops a bacterium’s ability to produce slime.
Aspirin does the same, by a different mechanism, as Domenico learned when he was studying slime at Winthrop-University Hospital, affiliated with SUNY-Stony Brook on Long Island. Having obtained a PhD from the University of Texas and done post-doctoral work at Rockefeller University and Louisiana State, he was in a lab, trying to determine how pneumonia bacteria cause disease.
“Someone turned me on to a machine that shakes and bakes bacteria to study their growth,” he recalls. When the machine’s computer tried to measure the growth of the samples, readings were inconsistent because of the slime, which made the bacteria clump and fall out of solution. “The product rep said, ‘Put a bit of aspirin in the liquid to keep the bacteria suspended,’” says Domenico, so he tried it. When he viewed the bacteria under a microscope, he found that the slime, which encapsulated the cells, had diminished, indicating that aspirin, like bismuth, has anti-slime properties.
“There are not too many other things on the planet that do this,” he says. “I’ve searched through thousands of chemicals.” He then began to search for ingredients to make Pepto-Bismol more potent.
Clinical trials have begun
A class of sulfur compounds called thiols proved to be the key. “Sulfur makes a bridge between organic molecules and metals,” he explains, drawing an oval with two hooks and a round bismuth molecule held by the hooks, like a crab holding onto a ball with both claws. In fact, the word ‘chelate’ derives from the Greek word for crab. Bismuth is chelated by these thiols, which makes the heavy metal more soluble and active. The oval part of the thiol represents a fatty, organic (hydrocarbon) compound, and the hooks are sulfur ions, which combine readily with bismuth. The fatty part has the capacity to diffuse through cell membranes and carry the bismuth to the interior of cells, where it displaces iron, blocking production of slime. Without slime, the bacteria cannot stick to surfaces, and they become vulnerable to destruction.
“The second I discovered bismuth-thiols in 1994,” says Domenico, “I thought, I did it! I can let go now. All this work has not been in vain, and I’ve made a difference. There was also an element of, ‘Now I’ll show them!’ You know, how everyone doubts you at first.”
It took nine years to perfect his invention. “At the start they were very smelly and difficult to work with, as sulfur compounds can be,” he says. He takes out a well-wrapped test tube containing a yellow powder. The initial smell is of a burnt match — another form of sulfur. On closer contact, the odor hints of rotten eggs, a problem when he first began making batches of the substance in his lab on Long Island. “The whole six-story building would evacuate,” he remembers. “People there hated me.”
He worked with many different thiols and discovered that each had different properties that could be used for specific applications, as for instance, when antifungal action is required. In 2001, a startup pharmaceutical company, Microbion Biosciences, approached him based on studies he published in medical journals. The Montana-based firm has just begun clinical trials of BTs.
While animal experiments have confirmed the efficacy of BTs for many medical applications, the initial focus in humans is via topical application on wounds. Treatment of tuberculosis, cystic fibrosis, and sinus infections with the use of mist inhaled from a nebulizer looks promising as well. BTs may also be effective against H. pylori, the bacteria implicated in ulcers.
Potential industrial applications for BTs include coating water filters, which get clogged with slime over time. Adding BTs to ship paint can prevent accumulation of bacteria that promote rust and drag on hulls, as well as the slime that invasive zebra mussels cling to as they hitch rides into new territories. During testing in Barbados, where almost one-third of crops are lost to plant infections, spraying with very low doses of BTs prevented 100 percent of infection.
However, these uses raise the question of environmental impact, which has not yet been fully studied. Bismuth is naturally contained in rock and dirt. Domenico says that in the environment, BTs break down rapidly into components that are harmless, and only low concentrations are required. He acknowledges that testing should be done before widespread use, but he believes that BTs will end up reducing human-caused toxicity by replacing far more toxic substances, such as the glutaraldehyde used in hydrofracturing to stop slime from gumming up sand filters in natural gas extraction.
Return to Woodstock
Now that the basic research phase is over, Microbion can’t afford to pay most of his salary. So Domenico is moving back to New York City with his wife, Gloria, to find work. They have spent the last year and a half in Woodstock, where the scientist finally met like-minded people: liberals, creative people, artists. “I’m really a sculptor,” he says, taking from a shelf two ceramic figures, a rotund little owl and a “slime creature”, a humanoid head with drooping features. “My father was an artist,” he says. “Art is what I do when I’m really happy.”
When BTs finally hit the market, and the royalties start rolling in, Domenico has every intention of retiring to Woodstock. “I know more people here than I’ve ever known,” he says.
Initial testing of new drugs is sometimes performed on patients who are beyond hope and expected to die. In this compassionate care setting, BTs were tested on people on the verge of having a leg amputated because of infection. In the cautious language of Microbion’s website, “Recent research has demonstrated that...treatment of chronic wounds with an antibiofilm strategy improves the chances of successful healing, which may lower the risk of amputation.”
“Even if this stuff never comes to market, I am comforted by knowing we improved the quality of life of terminally-ill patients,” says Domenico, “I’ll go to my grave feeling good about that.”++