New approach to tuberculosis treatment: targeting LD-transpeptidase enzyme

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 on Nov. 7 in Nature Chemical Biology.

At the root of their investigation, Gyanu Lamichhane, Ph.D. associate professor of medicine at the Johns Hopkins University School of Medicine 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.

Pankaj Kumar, Ph.D., postdoctoral fellow in infectious diseases at the Johns Hopkins University School of Medicine, 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 Lamichhane’s and Townsend’s 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, Amit Kaushik, Ph.D., a postdoctoral fellow in infectious diseases at the Johns Hopkins University School of Medicine, 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.

Townsend and Lamichhane say the focus of their research is now on creating variations of their original compound that are designed to target specific bacteria. The researchers are now in the process of initiating clinical trials to test the safety and efficacy of some of these new compounds.

Citation: Pankaj Kumar, Amit Kaushik, Evan P Lloyd, Shao-Gang Li,¬†Rohini Mattoo, Nicole C Ammerman, Drew T Bell, Alexander L Perryman, Trevor A Zandi, Sean Ekins, Stephan L Ginell, Craig A Townsend, Joel S Freundlich & Gyanu Lamichhane. “Non-classical transpeptidases yield insight into new antibacterials”. Nature Chemical Biology (2016)
DOI: http://dx.doi.org/10.1038/nchembio.2237
Research funding: National Institutes of Health, DOE/Office of Biological and Environmental Research
Adapted from press release by Johns Hopkins University School of Medicine.