Novel rRNA Assay Pinpoints Drugs That Shorten Time to TB Cure

By Marilynn Larkin

June 01, 2021

NEW YORK (Reuters Health) - A novel, non-culture-based assay called the ribosomal RNA synthesis (RS) ratio provides a molecular metric to assess the effects of candidate tuberculosis (TB) drugs, potentially accelerating the development of treatments that can cure TB faster, researchers say.

"Our team was motivated by a crucial roadblock to shorter TB treatments: lack of accurate markers of treatment effectiveness," Dr. Nicholas Walter of the University of Colorado Anschutz Medical Campus in Aurora told Reuters Health by email. "For decades, the conventional readout has been how drugs affect the burden of M. tuberculosis bacteria capable of growing in culture."

"Unfortunately," he said, "bacterial burden does not accurately predict the effectiveness of treatment, either in animals or humans."

"We discovered a new way of evaluating treatment effectiveness: evaluating a fundamental aspect of the bacterium's physiologic status (rRNA synthesis) rather than bacterial burden," he explained. As a result, a multidisciplinary team of scientists, called the Consortium for Applied Microbial Metrics (microbialmetrics.org), was assembled to build evidence for this approach.

As reported in Nature Communications, Dr. Walter and colleagues assessed the degree to which various TB drugs interrupt rRNA synthesis in experiments in culture, in mice and in sputum samples from TB patients.

They showed that sterilizing and nonsterilizing drugs have distinct impacts, such that sterilizing drugs and highly effective combination drug regimens profoundly suppress M. tuberculosis rRNA synthesis, whereas nonsterilizing drugs and weaker regimens do not.

Specifically, experiments showed that the sterilizing drugs rifampin and bedaquiline suppressed rRNA synthesis significantly more than the nonsterilizing drugs isoniazid, streptomycin, and ethambutol.

Rifampin decreased the RS ratio 130-fold in six hours and 546-fold in 48 hours. Bedaquiline also rapidly halted ongoing rRNA synthesis, decreasing the RS ratio sixfold in six hours and 149-fold in 48 hours.

In contrast, the three nonsterilizing drugs had only a limited impact on rRNA synthesis.

Dr. Walter said, "These new non-culture-based assays may complement or potentially replace existing culture-based markers. We are building evidence in a series of additional preclinical studies and human trials oriented toward the end goal of (the RS ratio) becoming a routine metric for antibiotic evaluation."

"The RS ratio has potential to serve as a marker for other chronic bacterial diseases," he added. "It is already shown to be a feasible tool that provides important new insight, so there are few barriers to immediate application."

Dr. Neil Schluger, Chairman, Department of Medicine at New York Medical College in Valhalla, New York commented in an email to Reuters Health, "This is a very exciting study that holds the potential to more rapidly and accurately assess the ability of novel drugs and regimens to transform treatment paradigms for patients with tuberculosis."

"Currently, new drugs and regimens are assessed by counting colony forming units of M. tuberculosis in sputum samples over time. This is a time-consuming and cumbersome approach that provides only a rough estimate of how drugs might work in actual clinical practice."

"By studying the physiological state of M. tuberculosis organisms rather than their sheer number," he said, "the RS ratio was shown in this study to potentially provide a more rapid and accurate estimate of the effectiveness of drugs."

The data in the paper are largely from in vitro and animal studies, he said. However, like Dr. Walter, he noted that the RS ratio is currently being examined in clinical trials in humans. "If the results hold up, this biomarker could be transformative in the rapid assessment of new treatments for TB," he concluded.

SOURCE: https://go.nature.com/2S0ARdF Nature Communications, online May 18, 2021.

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