Microbiology Research Could Lead to Improved TB Treatment

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-12-06-2005, Volume 0, Issue 0

A new understanding about how one class of bacteria protects itself from the environment could dramatically cut tuberculosis treatment time.

A new understanding of how certain kinds of bacteria build cell walls could lead to a breakthrough in tuberculosis treatment.

    An article in the Dec. 2 issue of Cell examines how mycobacteria, the category of bacteria that includes the pathogens behind tuberculosis and leprosy, grow into a communal structure called a biofilm.

    A biofilm forms when a community of bacteria grows together on a surface and is encompassed by a common extracellular matrix, according to Graham Hatfull, co-lead investigator from the University of Pittsburgh. In other types of bacteria, biofilm formation is linked to increased hardiness that makes antibiotic treatment very difficult or even impossible, he explained.

    When biofilms grow on prosthetic joints, the devices must be replaced because antibiotics will never kill the bacteria, according to Zhenkun Ma, the head of research at the Global Alliance for TB Drug Development.

    Hatfill speculated that tuberculosis bacteria might grow into a biofilm inside the bodies of patients, which would account for the treatment being so difficult. Eliminating the tuberculosis bacteria with antibiotics takes six to nine months, according to the Centers for Disease Control.

    “We don’t know if TB forms a biofilm in people but we think it does,” said co-lead investigator William Jacobs of Albert Einstein College. “When TB goes in the body, it hunkers down. Biofilms are a form of hunkering down.”

The Research

The study’s authors may be speculating about tuberculosis colonizing into biofilms, but they demonstrated that Mycobacteria smegmatis, a relative of tuberculosis that is easier to work with in the lab, does grow into biofilms. These structures are unusual because the common extracellular matrix is made out of long chains of fatty acids. In other classes of bacteria this structure is made of long chains of sugars.

    The researchers identified a gene, groEL1, which is essential for mycobacteria to turn into a biofilm. Mycobacteria normally produce very long fatty acids with 60 to 90 carbons, called mycolic acids, Hatfull explained. These are incorporated into the cell wall.

    When mycobacteria form biofilms they produce shorter chains of fatty acids, 58 to 68 carbons in length, Hatfull said. This usually occurs in the final stages of biofilm formation. These fatty acids may be involved in creating the encompassing matrix, he added.

    According to Jacobs, groEL1 is probably involved in processing proteins that are essential for switching to the shorter fatty acid chains, KasA and KasB. GroEL1 is a chaperone protein, a type of molecule that is necessary for folding other proteins into their proper formations.

    KasA and KasB were still present in cells where groEL1 was knocked out, but biofilm formation was impossible, Jacobs said. As a result he speculated that these two proteins were not able to get into their proper formations for fatty acid synthesis without the help of groEL1.

The Implications

This study does not provide evidence that tuberculosis bacteria grow into biofilms inside infected people. But it does show that M. smegmatis, another member of the same class does create biofilms. It also shows that groEL1, a protein present in all mycobacteria, is essential for biofilm formation.

    The next steps, according to Hatfull, are to determine whether biofilm formation is part of tuberculosis infections and whether groEL1 is involved in this process.

    If so, groEL1 could be a good drug target, he said. But even if it is not involved in tuberculosis pathogenesis, this knowledge could help researchers identify a different drug target down the road, he continued.

    If these findings about groEL1 and biofilm formation are extended to tuberculosis it could cut down on treatment time, said Mel Spigelman, R&D director at the TB Alliance. Knowing how to weaken the tuberculosis bacteria by preventing biofilm formation, if it occurs, could be a tremendous breakthrough.

    He said the research was “in a speculative mode but potentially very important.”

    It also might give scientists insight into how the leading drugs work to fight TB infection, he said.

    The leading TB drug, Nydrazid or Laniazid (isoniazid), inhibits the synthesis of the longer chains of fatty acids that are part of the tuberculosis bacterial cell wall, Hatfull said.