Drug-Resistant Tuberculosis Treatment by Using Tropical Plant Derivatives

Drug-Resistant Tuberculosis

A new preclinical study published on May 31, 2022, claims the discovery of a new class of medications that could be useful in treating individuals infected with drug-resistant Mycobacterium tuberculosis strains.

"The new class of PP derivatives is a Mycobacterium tuberculosis-targeted antibiotic with microbiome-safe features," stated senior author Ho-Yeon Song, Ph.D., of Soonchunhyang University in South Korea.

The findings were published in the journal PLOS Biology in an article titled "Discovery of Mycobacterium tuberculosis–Targeted antimicrobial PP derivatives."

Drug-resistant Tuberculosis

"While more testing is needed, the low effective dose and excellent degree of safety seen in these early tests suggest that these new medications will be crucial alternatives to the current tuberculosis treatment plan," Song added.

The researchers tested a number of natural compounds derived from plant extracts for antibacterial activity against M. tuberculosis as part of the investigation. Deoxypergularinine (DPG) was isolated and purified from the roots of Cynanchum atratum, a flowering plant used in traditional Chinese medicine.

The team has previously shown that this chemical suppressed not only regular M. tuberculosis but also drug-resistant forms of the bacterium in previous investigations. They also demonstrated that combining this active ingredient with the first line of traditional tuberculosis medications greatly lowered the minimum dosages (minimum inhibitory concentrations, MICs) of these treatments required to inhibit a bacterial strain (H37Ra).

Tuberculosis

The researchers created and evaluated numerous DPG analogs for their ability to suppress M. tuberculosis without hurting infected cells in the current investigation. They discovered a family of PP-derivatives containing phenanthrene and pyrrolidine groups in their structures that may efficiently inhibit M. tuberculosis while having little impact on infected cells, indicating low toxicity.

Several PP derivatives were found to be effective in cells infected with drug-resistant strains of the bacterium in the culture at concentrations lower than those employed for current first-line tuberculosis treatments, indicating that these derivatives have stronger antibacterial power.

"PPs displayed antitubercular effects in macrophage and tuberculosis mice models, with no observable harm in all tests performed," according to the scientists.

DR-TB

The researchers showed that giving sick rodents three PP derivatives (PP1S, PP2S, and PP3S) for four weeks reduced the burden of tuberculosis infection compared to untreated mice. Furthermore, after two weeks of high-dose treatment and four weeks of intermediate-dose treatment, the rats showed no detrimental effects.

Because antibiotic treatments are commonly associated with the off-target killing of helpful or innocuous bacteria that inhabit the human gut, the authors also examined the effects of the PP derivative on the intestinal microbiome in mice.

"PPs specifically suppressed M. tuberculosis without appreciably affecting the gut microbiota in mice," the authors said. PP2S treatment for a week showed no substantial loss in gut flora, whereas conventional medicines affected the mouse gut microbiota

In vitro investigations were also carried out to determine the medication target. They discovered that the drug's genetic target is a gene called PE-PGRS57, which is only found in the genomes of the M. tuberculosis complex. This explains the new class of drugs' exceptional selectivity and safety potency.