December 2, 2022

Drug candidates are safer and more effective than current therapies

infection by Mycobacterium tuberculosis kills 1.5 million people worldwide each year. There are antibiotics to treat tuberculosis, but in recent years multidrug resistant (MDR), ultradrug resistant (XDR) and totally drug resistant (TDR) strains of the bacteria have developed. According to a new study published on May 31st in the open access journal PLOS Biology by Ho-Yeon Song of Soonchunhyang University in the Republic of Korea and colleagues, a new class of antibiotics is highly effective against drug-resistant tuberculosis. If validated in clinical trials, the new class of drugs would represent a major advance in the treatment of tuberculosis.

To develop new drug candidates, the authors first screened a wide variety of plant extracts and found one with particularly promising antibacterial activity. Deoxypergularinine (DPG) is purified from the root of Cynanchum atratum, a flowering plant used in traditional Chinese medicine. Researchers proceeded to manufacture and test several analogs of DPG for their ability to inhibit Mr. tuberculosis without harming the cells it has infected. They identified a class of derivatives (collectively called PP, based on the presence of phenanthrene and pyrrolidine groups in the structures) with high antituberculosis effects and low toxicity.

For several derivatives, a standard measure of antibacterial effect, known as the minimum inhibitory concentration (MIC), was lower (i.e., better) than for current first-line anti-tuberculosis drugs in a culture. cell infected with the XDR strain. In a mouse model, 4 weeks of treatment with a derivative, called PP1S, significantly reduced the burden of tuberculosis infection compared to the control group. Neither PP1S nor a second derivative, PP2S, produced clinical side effects in healthy rats after two weeks of high dose treatment. No adverse effects were observed after four weeks of mid-dose treatment with PP2S.

One of the problems with antibiotic treatment is the off-target killing of other bacteria, including those in the gut. After one week of treatment with PP2S, no significant changes were observed in the gut microbiome of mice, compared to the multiple changes seen after treatment with other anti-tuberculosis drugs. The extremely selective effect on Mr. tuberculosis is likely due to the PP target, which the authors showed was likely a gene called PE_PGRS57. This gene appears to be found in very few other species of bacteria, including several other Mycobacterium species.

Currently, the treatment of multidrug-resistant tuberculosis requires more than a year of treatment with a cocktail of antibiotics, each with significant side effects. “Although further testing is needed, the low effective dose and high level of safety of these early tests indicate that these new drugs are likely to be important alternatives to the current TB treatment regimen,” Song said.

Song adds: “A new class of derivatives of PP is a Mycobacterium tuberculosis-targeted antimicrobial with properties that are safe for the microbiome.”

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