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Blocking a Mycobacterial Protein Could Help Fight TB

Blocking a single protein in mycobacteria causes individual bacterial cells to become more alike, leaving them more vulnerable to rapid killing by antibiotics, a new study shows. These findings may hold promise for improving tuberculosis (TB) treatment. E. Hesper Rego, PhD, from Yale University, New Haven, Connecticut, and colleagues published their findings online in Nature.
“Our results show that mycobacteria encode a non-conserved protein that controls the pattern of cell growth, resulting in a population that is both heterogeneous and better able to survive antibiotic pressure,” the authors write.
In an interview with Contagion®, corresponding author Eric J. Rubin, MD, PhD, Irene Heinz Given Professor of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health, Boston, Massachusetts, emphasized that treatment for TB is a long process, and typically takes at least 6 months for drug-sensitive cases, and even longer if drug resistance is present. “We are generally interested in finding ways that might shorten that,” he said.  
According to Dr. Rubin, individual mycobacterial organisms all differ in their size and shape, even if they come from the same, genetically identical population. “We and others have also found that the rate of killing by antibiotics varies” among individual organisms, he noted.
The researchers, therefore, set out to investigate the reasons for this variation, and how variability relates to survival of the mycobacterial population. They used fluorescent reporter molecules and time-lapse microscopy to examine individual mycobacterial cells as they grew and divided. “We largely studied an organism called Mycobacterium smegmatis, a relative of the bacterium that causes TB, Mycobacterium tuberculosis,” said Dr. Rubin.
The study showed that each individual mycobacterial organism in a population stained differently with a fluorescent dye. It also showed that the fluorescence intensity of individual organisms correlated closely with how quickly they were killed by rifampin, an antibiotic that is used to treat TB.  
The researchers then searched for bacterial mutants that either increased or decreased staining, and focused on one particular mutant that lacked a protein known as LamA (Loss of Asymmetry Mutant A).  
“Cells that lack LamA grow perfectly normally,” said Dr. Rubin, “however, they lose many of the differences that distinguish individual cells. And they are killed more uniformly by antibiotics.”
Overall, this results in more rapid mycobacterial killing by a variety of antibiotics, he added. “And this is true in both M. smegmatis and M. tuberculosis.”
While typical antibacterial therapies target critical proteins and structures in pathogenic bacteria, the results of this study offer a somewhat different treatment strategy for TB. “A drug that prevented LamA from performing its function would be expected to have little effect by itself,” said Dr. Rubin, “but when coupled with effective antibiotics, this could lead to much more rapid killing of bacteria and, hopefully, cure.”
“The key experiments underway right now are to see if what we see in a test tube is also true during an experimental infection,” said Dr. Rubin. “If so, we would like to start screening for inhibitors of LamA,” he concluded.
Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.
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