Triclosan added to consumer products alters response to antibiotic treatment

The study, available online February 19 in the newspaper Antimicrobial agents and chemotherapy, suggests that exposure to triclosan could inadvertently lead bacteria to a state in which they would be able to tolerate concentrations of normally lethal antibiotics, including antibiotics commonly used to treat urinary tract infections.

Triclosan is the active ingredient responsible for the "antibacterial" property marketed on many consumer products. It is added to toothpastes, mouthwashes, cosmetics and even clothing, baby toys and credit cards to reduce or prevent bacterial growth.

"In order to effectively kill bacterial cells, triclosan is added at high concentrations in the products," said Petra Levin, a professor of biology at the Arts and Sciences.

In 2017, the US Food and Drug Administration discussed both safety concerns and lack of efficiency by recommending that triclosan not be added to consumer soap products, but these guidelines did not deter add it to other products. What's more, Levin said, "Triclosan is very stable, it stays in the body and in the environment for a long time."

The new study in mice reveals how much exposure to triclosan limits the body's ability to respond to antibiotic treatment of urinary tract infections. It also brings new insights into the cellular mechanism that allows triclosan to interfere with antibiotic treatment.

Escape from death

Some antibiotics kill bacterial cells, while others prevent them from growing.

Levin and his colleagues were particularly interested in bactericidal antibiotics – those that can kill bacterial cells and are usually prescribed by doctors to treat bacterial infections. They wanted to know if triclosan could protect bacteria from death in the presence of deadly antibiotics.

Corey Westfall, a postdoctoral researcher at Levin Lab, treated bacterial cells with bactericidal antibiotics and monitored their ability to survive over time. In one group, the bacteria were exposed to triclosan prior to the administration of the bactericidal antibiotic. In the other group, they were not there.

"Triclosan has dramatically increased the number of surviving bacterial cells," said Levin. "Normally, one in a million cells survive antibiotics, and a healthy immune system can control them, but triclosan changes the number of cells, and instead of just one in every one million bacteria surviving, one in ten survives after 20 hours, now the immune system is out of date. "

The exposure to triclosan allowed the bacteria to escape death thanks to antibiotics. And the protective property is not limited to a single family of antibiotics. In fact, several antibiotics considered unique in their way of killing cells were less effective in killing bacteria exposed to triclosan.

"Triclosan has increased tolerance to a wide range of antibiotics," said Westfall. "Ciprofloxacin (also called Cipro) was the most interesting for us because it is a fluoroquinolone that interferes with the replication of DNA and is the most common antibiotic used to treat urinary tract infections. "

Antibiotics can not do their job with triclosan

Urinary tract infections occur when bacteria, mainly Escherichia coli (E. coli), enter and infect the urinary tract. Antibiotics such as Cipro are commonly used to kill bacteria and treat the infection.

Urinary tract infections are common. the same goes for exposure to triclosan. In the United States, a shocking percentage – about 75% – of adults have detectable levels of triclosan in their urine. About 10% of adults have levels high enough to prevent the growth of E. Coli. Could the presence of triclosan in the body affect the treatment of urinary tract infections?

Westfall and Levin worked with faculty of medicine at the University of Washington in St. Louis to answer this question.

Ana Flores-Mireles, Assistant Professor at the University of Notre Dame, worked on this study as a postdoctoral researcher in the laboratory of Scott Hultgren, Professor Helen L. Stoever of Molecular Microbiology at the Faculty of Medicine. With the help of Jeffrey Henderson, an associate professor of medicine and molecular biology, she discovered that mice who drink triclosan – enriched water have triclosan levels in the urine similar to those observed in humans.

"This result allowed us to test the impact of triclosan levels in human urine during antibiotic treatment of urinary tract infections in mice," Levin said.

All infected mice received Cipro to treat UTI. Only some mice drank water enriched with triclosan. After the antibiotic treatment, mice exposed to triclosan had a large number of bacteria in their urine and sticked to the bladder; the mice without exposure had significantly lower bacterial counts.

"The magnitude of the difference in bacterial burden between mice that drank triclosan-enriched water and those that did not take it is striking," Levin said.

"If the difference in the number of bacteria between groups was less than ten times, it would be difficult to prove that triclosan was the culprit," added Levin. "We found 100 times more bacteria in the urine of mice treated with triclosan, that's a lot."

This striking result has an equally striking message: antibiotics are less effective in treating urinary tract infections in the presence of triclosan, at least in mice.

The dirty weapon of Triclosan: ppGpp

Triclosan interferes with antibiotic treatment, but how?

Levin and his colleagues discovered that triclosan works with a cell growth inhibitor, a small molecule called ppGpp, to make cells less susceptible to antibiotics.

During periods of stress, ppGpp reacts by closing the biosynthetic pathways that make up the building blocks – DNA, RNA, protein and fat – that eventually become new cells. This answer helps to divert resources from growth to survival.

"There is a rule in medicine that you do not give drugs that slow cell growth before drugs that kill cells," said Levin.

Bactericidal antibiotics kill by targeting specific biosynthetic pathways. Ampicillin targets the enzymes that make up the bacterial cell wall, for example, while Cipro targets the synthesis of DNA. When these pathways are closed, bactericidal antibiotics find it difficult to do their job.

If triclosan triggers ppGpp, biosynthesis is reduced and bactericidal antibiotics become ineffective at killing cells. Biosynthesis continues in bacteria lacking ppGpp, and these cells should die.

Levin and his colleagues tested their hypothesis by engineering E mutants. Coli unable to make ppGpp and compared them to an E. coli capable of making ppGpp. The absence of ppGpp in mutant E. coli prevented triclosan from protecting cells against bactericidal antibiotics.

Clinical studies would be needed to definitively prove that triclosan interferes with antibiotic treatments in humans, said Levin: "I hope this study will serve as a warning that will help us rethink the disease. importance of antimicrobials in consumer products. "

Explore further:
Minnesota prohibits antibacterial chemical triclosan in soaps

More information:
Corey Westfall et al., The widely used antimicrobial triclosan induces high levels of antibiotic tolerance in vitro and reduces their efficacy up to 100 times in vivo. Antimicrobial agents and chemotherapy (2019). DOI: 10.1128 / AAC.02312-18