Targeting new enzyme to treat tuberculosis

Targeting new enzyme to treat tuberculosis

Researchers at Johns Hopkins report they have laid the foundation to develop novel antibiotics that work against incurable, antibiotic-resistant bacteria like tuberculosis by targeting an enzyme essential to the production and integrity of bacterial cell walls.
The findings, they say, suggest that antibiotic drugs specifically targeting the recently discovered LD-transpeptidase enzyme, which is needed to build bacterial cell walls in some bacteria, could potentially cure many antibiotic-resistant infections.

An additional implication of the research, the Johns Hopkins team says, is that drugs targeting the enzyme could offer quicker, cheaper and more easily accessible treatment against tuberculosis, a disease that still kills more people worldwide than any other infection, according to the Centers for Disease Control and Prevention.
A summary of the findings is published in Nature Chemical Biology.
At the root of their investigation, senior author says, is the fact than more than half of antibiotics prescribed today are of a class called beta-lactams, which work by interrupting the function of the DD-transpeptidase enzyme that creates bacterial cell walls. Without it, bacteria quickly die. However, in 2005, a team of researchers found a second wall-building enzyme, LD-transpeptidase, that allows bacteria like the ones that cause TB to survive antibiotic treatments. "We looked at the structure of LD-transpeptidase, thought about how it works and started making new compounds that could be used against it," says another author.

They began the research in the new study by extracting LD-transpeptidase from many species of bacteria and examining its detailed molecular structure with a sophisticated imaging system known as protein X-ray crystallography using the Advanced Photon Source at the Argonne National Laboratory in Chicago.

By analyzing the enzyme's structure, Johns Hopkins researchers were able to design new compounds in the carbapenem group, a subclass of the beta-lactam antibiotics that bind to the LD-transpeptidase wall-building enzyme and stop its function.

In live bacterial cultures, the carbapenems were shown by research groups to stop the enzyme's wall-building activity. The new compounds were even effective against the ESKAPE pathogens, a group of six bacterial species that the Centers for Disease Control and Prevention has identified as a threat because of their propensity for developing antibiotic resistance.

Following these successes, they tested two carbapenems in vivo against TB in mice infected with TB. Researchers infected mice with tuberculosis bacteria and separated them into different treatment groups. The rodents' lungs were sampled periodically over a period of three weeks, and the results showed that even without use of classic TB antibiotic treatments, the new carbapenems, specifically biapenem, cured TB infection in mice.

Many commonly prescribed antibiotics today work on a broad spectrum of bacterial species, meaning that in addition to killing off bad bacteria, they also destroy the friendly bacteria our bodies need to function normally and whose destruction can cause dangerous side effects. Senior author believes that the future of antibiotic treatments relies on our ability to be good antimicrobial stewards and treat specific bacteria without affecting our bodies' natural microbiome. Not only will this cut down on antibiotic side effects, but it will also slow the development of antibiotic resistance in the bacterial species not being targeted.

The researchers are now in the process of initiating clinical trials to test the safety and efficacy of some of these new compounds.