We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress hp
Sign In
Advertise with Us
Sekisui Diagnostics UK Ltd.

Download Mobile App




New Version of Old Drug Shows Promise for Treating Drug-Resistant Tuberculosis

By LabMedica International staff writers
Posted on 15 Jun 2015
Print article
Image: DNA polymerase forms a homodimeric ring (shown as blue cartoon and surface representation). Each polypeptide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground) (Photo courtesy of the Helmholtz Centre for Infection Research).
Image: DNA polymerase forms a homodimeric ring (shown as blue cartoon and surface representation). Each polypeptide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground) (Photo courtesy of the Helmholtz Centre for Infection Research).
A team of molecular microbiologists has determined the mechanism by which the Streptomyces-derived antibiotic griselimycin blocks the growth of Mycobacterium tuberculosis, the bacterium responsible for causing more than eight million cases of tuberculosis annually on a worldwide basis.

Investigators from the Helmholtz Center for Infection Research (Braunschweig, Germany), other German research institutes, and the biomedical company Sanofi (Paris, France) were interested in exploring the possibility of using griselimycin or one of its derivatives for treating drug resistant tuberculosis; while this drug had been evaluated in the 1960's it had suffered in comparison to others. However, M. tuberculosis has developed resistance to most of those other drugs, and development of replacements is a top priority.

The investigators reported in the June 5, 2015, issue of the journal Science that a variant of griselimycinm, cyclohexylgriselimycin, was particularly effective against M. tuberculosis, in cells and when administered orally to an animal model.

The effectiveness of cyclohexylgriselimycin was found to be due to the drug's inhibition of the M. tuberculosis DNA polymerase sliding clamp DnaN. A DNA clamp, also known as a sliding clamp, is a protein fold that serves as a processivity-promoting factor in DNA replication. Processivity is an enzyme's ability to catalyze consecutive reactions without releasing its substrate. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.

As inhibiting the DNA clamp is a completely different mechanisms from those of antibiotics now used against tuberculosis and other bacterial pathogens, the investigators consider that the risk of developing resistance to cyclohexylgriselimycin is low.

"We hope that cyclohexylgriselimycin will become an agent that can even be used against resistant tuberculosis pathogens in the future and contributes to a more successful fight against this dreadful disease," said senior author Dr. Rolf Müller, head of the department of microbial natural products at the Helmholtz Centre for Infection Research. "In the tuberculosis pathogen, the substance binds to the so-called DNA clamp and thus suppresses the activity of the DNA polymerase enzyme, which multiplies the genetic information inside the cell. We resumed the work on this agent and optimized it such that it shows excellent activity in the infection model—even against multi-resistant tuberculosis pathogens."

Related Links:

Helmholtz Centre for Infection Research
Sanofi


New
Gold Member
ANA & ENA Screening Assays
ANA and ENA Assays
Unit-Dose Packaging solution
HLX
New
Adenovirus Detection Kit
REALQUALITY RQ-ADENO
New
Quantitative Immunoassay Analyzer
AS050

Print article

Channels

Clinical Chemistry

view channel
Image: The new saliva-based test for heart failure measures two biomarkers in about 15 minutes (Photo courtesy of Trey Pittman)

POC Saliva Testing Device Predicts Heart Failure in 15 Minutes

Heart failure is a serious condition where the heart muscle is unable to pump sufficient oxygen-rich blood throughout the body. It ranks as a major cause of death globally and is particularly fatal for... Read more

Molecular Diagnostics

view channel
Image: The bowel cancer breakthrough could result in better treatment outcomes (Photo courtesy of 123RF)

New RNA Molecules Can Help Predict Bowel Cancer Return Recurrence

Colorectal cancer accounts for 10% of all cancer-related deaths worldwide and was ranked as the second most common cause of cancer death in the United States in 2022. Currently, clinicians face diagnostic... Read more

Hematology

view channel
Image: QScout CBC will give a complete blood count in 2 minutes from fingerstick or venous blood (Photo courtesy of Ad Astra Diagnostics)

Next Gen CBC and Sepsis Diagnostic System Targets Faster, Earlier, Easier Results

Every hour is critical in protecting patients from infections, yet there are currently limited tools to assist in early diagnosis before patients reach a hospital. The complete blood count (CBC) is a common... Read more

Microbiology

view channel
Image: The InfectoSynovia test has the potential to revolutionize the diagnosis of periprosthetic joint infection (Photo courtesy of 123RF)

High-Accuracy Bedside Test to Diagnose Periprosthetic Joint Infection in Five Minutes

Periprosthetic joint infection (PJI) represents a significant global issue that is worsening as the number of joint replacements increases due to aging populations. In the United States alone, the anticipated... Read more

Pathology

view channel
Image

AI-Based Method Shows Promise for Pathological Diagnosis of Hereditary Kidney Diseases

Alport syndrome is a hereditary kidney disorder characterized by kidney dysfunction, sensorineural hearing loss, and ocular abnormalities. Early in the disease, patients experience hematuria, which is... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.