Multi-resistant tuberculosis is being combated with herbal active ingredients in preclinical studies

An international research team led by scientists at the University of British Columbia has demonstrated how to create a novel semi-synthetic compound from sanguinarine (SG), an alkaloid derived from the flowering plant Sanguinaria canadensisshows strong activity against Mycobacterium tuberculosis (Mtb), the pathogen that causes tuberculosis (TB), including multidrug-resistant (MDR) clinical isolates. The compound, called BPD-9, was inactive against a range of other gram-negative and gram-positive bacteria, suggesting narrow-spectrum activity Mycobacterium Species. Preclinical in vivo studies showed that BPD-9 also exhibited antibacterial activity M. bovis BCG in infected mice. The researchers say the new compound structure could provide a promising chemical scaffold for developing effective new drugs against tuberculosis.

“Our results reveal a new chemical substance with unique combat properties Mycobacterium tuberculosiswhich may be further exploited for clinical translation,” said Jim Sun, PhD, assistant professor in the Department of Microbiology and Immunology at the University of British Columbia. Sun is corresponding author of the team's published article in spectrum of microbiology, titled, “Discovery of Benzo[c]Phenanthridine derivatives with strong activity against multidrug-resistant drugs Mycobacterium tuberculosis“, in which the team concluded: “The unique specificity of BPDs for Mycobacterium spp. and their effectiveness against MDR-Mtb isolates suggest a possible new mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-tuberculosis drug discovery.”

M. Tuberculosis is the most common cause of death related to bacterial diseases worldwide, the authors write. However, current antibiotic therapies used to treat tuberculosis are outdated, require longer courses of treatment, and carry the risk of developing drug resistance. “There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug resistance Mycobacterium Tuberculosis (Mtb),” the team explained.

For their new study, the researchers conducted a search for novel targeted antibiotics M. Tuberculosis that could be effective against drug-resistant strains. A valuable starting point for the search for new antibiotics in drug research is the world of natural products. “In order to find new mechanisms of action and new chemical scaffolds, natural products offer a number of advantages for drug development,” the researchers emphasized. “Natural products are ideal candidates for drug research due to their unique structural and scaffold diversity.”

The team focused on sanguinarine, a natural benzo[c]Phenanthridine alkaloid compound with known antimicrobial properties derived from an herbaceous flowering plant native to North America. Sanguinarine is used in traditional and alternative veterinary medicine, but is not suitable for use as a medicine in humans due to its toxicity. Sanguinarine has shown antibacterial activity against various gram-positive and gram-negative bacteria. They pointed out: “However, the antibacterial effect of SG against mycobacteria has not been explored and may represent a missed opportunity.”

Sun and colleagues reengineered sanguinarine using principles of medicinal chemistry to produce a more potent antibacterial compound with lower toxicity. “…we designed and synthesized 35 unique derivatives of SG,” they explained. “Phenotypic activity screening identified five hits within this group of new compounds that exhibited significantly improved anti-Mtb activity compared to SG.”

The two most potent compounds, BPD-6 and BPD-9, demonstrated low micromolar inhibitory activity against several mycobacterial species. In studies in test tubes and in mice, BPD-9 was able to kill strains of M. Tuberculosis that are resistant to all first-line antibiotics used in the clinic to treat tuberculosis. “Importantly, BPD-9 was active against several multidrug-resistant (MDR) clinical Mtb isolates and demonstrated antimycobacterial activity against them in vivo M. bovis BCG in infected mice,” the researchers wrote. In addition, BPD-9 was effective against non-replicating (dormant) and intracellular M. TuberculosisThese are two key aspects that limit the effectiveness of current anti-TB drugs. “We provide biological evidence that these compounds inhibit metabolically inactive, non-replicating Mtb, intracellular Mtb and several clinical MDR-TB strains at the low micromolar range,” they added.

The researchers also found that BPD-9 was only effective against pathogenic bacteria of the same genus M. Tuberculosispotentially sparing the microbiome and other beneficial bacteria that most antibiotics damage.

Sun concluded: “Our determination is that the new compound is effective against other members of the group Mycobacterium This genus could also prove valuable in the fight against fatal lung infections caused by non-tuberculous mycobacteria, which are known to be resistant to most antibiotics. It's also tempting to speculate that BPD-9 could be deadly Mycobacterium tuberculosis in a manner that differs from that of existing anti-TB drugs.” In their paper, the authors noted: “The selective ability to inhibit multiple species Mycobacterium also supports a target that is unique to this genus…The potency, specificity and cytotoxicity are all superior to sanguinarine and suggest a unique mode of action distinct from all first-line tuberculosis antibiotics…”.