Anchors Provide Novel Way to Hijack Superbugs

    Scientists at Monash University of Australia may have found a way to stop deadly bacteria from infecting patients. The discovery could lead to a whole new way of treating antibiotic-resistant “superbugs.” The researchers have uncovered what may be an Achilles heel on the bacteria cell membrane that could act as a potential novel drug target.

    The Monash team focused on urinary tract infections because almost 50% of women will suffer at least one infection during their lifetime, primarily caused by Escherichia coli. The bacterium travels along the urethra to the bladder where it triggers painful infections. To colonize the bladder efficiently—which is constantly being flushed out with urine—bacteria have developed a series of nanofilaments, called fimbriae or attachment pili, that effectively anchor the bacteria to the walls of the urinary tract.

    The study investigators found that a specific protein called translocation and assembly module (TAM) was essential for the assembly of the anchoring filaments. Moreover, the researchers describe how they developed an assay to measure the assembly of the filament-forming protein, called an usher.

    “Using our assay we tested whether blocking TAM had any effect on usher,” explained senior study author Trevor Lithgow, Ph.D., professor at the Biomedicine Discovery Institute within Monash University. “What we found was that TAM is required for the assembly of usher and therefore for the production of the filaments needed to anchor the bacteria to the urinary tract surface.”

    The findings from this study were published recently in Nature Microbiology in an article entitled “Effective Assembly of Fimbriae in Escherichia coli Depends on the Translocation Assembly Module Nanomachine.”

    The assay revealed that, under normal circumstances, E. coli can create filaments within 2 minutes of sensing the urinary tract environment. However, when TAM is blocked, it can take up to 4 hours for the same anchoring process to happen.

    “We report that a rapid response in usher assembly is crucially dependent on the translocation assembly module,” the authors wrote. “We assayed the assembly reaction for a range of ushers and provide mechanistic insight into the β-barrel assembly pathway that enables the rapid deployment of bacterial fimbriae.”

    The scientists also noted that the discovery of how TAM impacts the E. coli’s ability to latch onto the wall of the urinary tract could be a very important target for drug therapy.

    “Most antibiotics against E. coli have to get across the bacterial cell membranes in order to kill the invader,” Dr. Lithgow remarked. “The TAM is on the bacterial surface, so it is directly accessible to the sorts of drugs that would inhibit its function, and thereby halt the rapid production of these nanofilaments.”

    Moreover, other potentially lethal bacteria also use filaments that are controlled through TAM. These include Klebsiella pneumoniae carbapenemase-producing bacteria (KPC), an antibiotic-resistant superbug that is thought to have contributed to numerous deaths in the past several years.