By Stephen D’Angelo, Cornell Research & Innovation

Researchers have identified a new way to fight infections like Lyme disease and syphilis by disrupting the bacteria’s ‘motor,’ preventing it from spreading through the body.

The findings could have wide-ranging impacts on the treatment of infections in the future as concern about antibiotic-resistant strains grows. The study was published in ACS Chemical Biology.

“Many types of bacteria must be able to move to infect their host organisms, including humans,” said Brian Crane, director of the Weill Institute for Cell and Molecular Biology, corresponding author on the publication.

“Motility can be important to move between hosts—ticks to humans, for example—and also for disseminating within the host, colonizing the most advantageous tissue, and evading the immune system.”

Disrupting the ability to move

In the study, funded by the National Institutes of Health and the Bay Area Lyme Foundation, the researchers exploited a crucial relationship in the bacteria’s movement system by disrupting the germ’s ability to propel itself through tissues, and significantly weakening its chances to spread and infect.

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Credit: Credit Chunhao Li

Spirochetes are thin, corkscrew-shaped bacteria that spiral through body tissues using a hidden propeller-like motor, protected by a membrane that shields it from the host’s immune system.

Central to its ability to accelerate is a long strand called a flagella that is joined by a hook to the organism’s motion-generating machinery. Built from self-assembled protein subunits called FlgE, the hook is tightly held together by molecular bridges known as lysinoalanine (LAL) cross-links.

“When LAL formation is disrupted, a spirochetes’ flagella hook and motor are unable to work together to move effectively. This, in turn, prevents the spirochete from swimming through body tissues and significantly reduces the ability to spread and infect,” said Michael Lynch, research associate in the Crane Group (A&S), a Cornell Weill Institute lab, and the study’s first author.

After testing a collection of existing, clinically approved drug compounds, the researchers identified three—hexachlorophene, triclosan, and dichlorophene—that could be used as inhibitors to interfere with the connections between LAL molecules and the flagella hook.

A new way to fight infections

In one experiment on the spirochete linked to gum disease, treatment with hexachlorophene significantly reduced the bacteria’s ability to move, demonstrating that stopping their motility could be a powerful new way to fight infections.

Spirochetes, including Borrelia (Lyme disease), Treponema (syphilis), and Leptospira (leptospirosis, a bacterial infection that causes mild flu-like illness to severe kidney or liver damage), are highly invasive and capable of penetrating virtually every tissue in the human body, even crossing the blood-brain barrier.

According to the researchers, many of these infections are persistent, difficult to diagnose early, and sometimes resistant to standard medicines. Current treatments rely primarily on antibiotics, which target bacteria and cells indiscriminately, affecting both harmful and beneficial bacteria.

“In contrast, our approach is highly specific, targeting the formation of LAL in flagella within pathogenic spirochetes—the only known bacteria that catalyze the formation of LAL cross-links between flagella subunits,” Lynch said. “This specificity has the potential to reduce collateral damage to beneficial bacteria, such as microbiota in the gut microbiome, which is a significant advantage over conventional antibiotic treatments.”

Antibiotic resistence

According to the researchers, the need for novel antimicrobial strategies to combat spirochetes is pressing, as antibiotic-resistant strains evolve and emerge. This puts available drug options for individuals, and even public health efforts combating certain diseases, at risk, they said.

The researchers’ approach focusing on bacteria mobility could expand the number of targets for antibiotic drug development, helping to address the challenge that disease-causing bacteria are developing resistance to today’s common antibiotics.

“While bacterial motility has been studied extensively, this is the first research to target LAL cross-links in the flagella hook as an antimicrobial strategy,” Crane said. “Ultimately, because motility is widely recognized as an enhancement in pathogenic spirochetes’ ability to cause disease, our results establish LAL cross-linking as a legitimate target for antimicrobial therapeutic development.”

SOURCE: Cornell Research & Innovation