Drug candidates are safer and more effective than current therapies

infection by Mycobacterium tuberculosis kills 1.5 million people worldwide every year. There are antibiotics to treat tuberculosis, but multidrug-resistant (MDR), ultra-resistant (XDR) and totally drug-resistant (TDR) strains of bacteria have emerged in recent years. According to a new study published on DecSt 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.

In order to develop new drug candidates, the authors first screened a wide variety of plant extracts and found one with a particularly promising antibacterial effect. Deoxypergularinin (DPG) is purified from the root of Cynanchum atratum, a flowering plant used in traditional Chinese medicine. Researchers went on to make and test several DPG analogs for their inhibitory ability Mr tuberculosis without damaging the infected cells. They identified a class of derivatives (collectively referred to as PP based on the presence of phenanthrene and pyrrolidine groups in the structures) with high antituberculosis activity and low toxicity.

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

One of the problems with antibiotic treatment is the untargeted 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 numerous changes observed 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 to be likely a gene called PE_PGRS57. This gene appears to be found in very few other species of bacteria, including some other species of Mycobacterium.

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

Song adds: “A new class of PP derivatives is a Mycobacterium tuberculosis– Targeted antimicrobial with properties that are harmless to the microbiome. »

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