A new preclinical study conducted on rat models and published on May 31, 2022, reports the discovery of a new class of drugs that could prove effective in treating patients infected with drug-resistant strains of Mycobacterium tuberculosis.

Senior author of the study, Ho-Yeon Song, PhD, of Soonchunhyang University in South Korea said, “The new class of PP derivatives is a Mycobacterium tuberculosis-targeted antimicrobial with microbiome-safe properties.”

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

“While further testing will be required, the low effective dose and high level of safety in these early tests indicate that these new drugs are likely to be important alternatives to the current regimen for treatment of tuberculosis,” Song said.

As part of the study, the scientists screened a variety of natural products derived from plant extracts for potent antibacterial activity against M. tuberculosis. This led them to isolate and purify deoxypergularinine (DPG) from the roots of Cynanchum atratum, a flowering plant used in traditional Chinese medicine.

In earlier studies, the team showed that this compound inhibited not only normal M. tuberculosis but also drug-resistant strains of the bacterium. They had also shown, combining this active ingredient with the first line of standard drugs used to treat tuberculosis, significantly reduced the minimum doses (minimum inhibitory concentrations, MICs) of these drugs needed to inhibit a strain of the bacterium (H37Ra).

In the current study, the team developed and tested multiple analogues of DPG for their ability to inhibit M. tuberculosis without harming the infected cells. They identified a class of PP-derivatives, characterized by the presence of phenanthrene and pyrrolidine groups in their structures, that could inhibit M. tuberculosis effectively with negligible effects on the cells infected, indicating their low toxicity.

The team found several PP derivatives were effective at concentrations lower that that used for current first-line tuberculosis drugs in cells infected with drug-resistant strains of the bacterium in culture, indicating higher antibacterial potency of these derivatives.

The authors notes, “PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested.”

The team treated infected rats with three PP derivatives (PP1S, PP2S and PP3S) separately for 4 weeks and found this reduced the burden of tuberculosis infection compared to untreated mice. Moreover, the treatments produced no adverse effects in the rats upon two weeks of high-dose treatment and four weeks of intermediate-dose treatment.

The authors also tested the effects of the PP derivative on the intestinal microbiome in mice, since antibiotic treatments are generally associated with off-target killing of beneficial or harmless bacteria that colonize the human gut.

The authors noted, “PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice.” Whereas standard drugs compromised the mouse gut microbiome, treatment with PP2S for a week showed no significant reduction in gut bacteria.

The team also conducted in vitro studies to identify the drug target. They found a gene called PE-PGRS57, that is found only in the genomes of the M. tuberculosis complex, to be the genetic target of the drug. This explains the high selectivity and safety potency of these new class of compounds.

Mycobacterium tuberculosis infects and kills nearly 1.5 million people each year globally. Current standard care for drug-susceptible tuberculosis includes a four-month regimen of rifapentine-moxifloxacin or a six-to-nine-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE), according to the US Centers for Disease Control and Prevention (CDC).

Several factors including incomplete treatment course, and wrong dosage or period of treatment, has led to the emergence of multi-drug resistant (MDR), pre-extensively drug-resistant (pre-XDR), extensively drug-resistant (XDR) and totally drug-resistant (TDR) strains of Mycobacterium tuberculosis. If successfully tested in clinical trials, the new class of deoxypergularinine derivates would represent a major advance in treating tuberculosis.

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