February 2019 | Issue 40
A new drug breakthrough for Buruli ulcer treatment

Anne.jpgAnne Loh, Assistant Director, Communications & Outreach


“It’s not every day that we discover a new drug,” said LKCMedicine Associate Professor of Infectious Disease Kevin Pethe. He should know, having spent his career working on drug discovery for multi-drug resistant tuberculosis (TB). In 2013, A/Prof Pethe discovered drug candidate Q203, an imidazopyridine amide, while working at Institut Pasteur Korea. Since joining LKCMedicine in 2014, A/Prof Pethe has been researching antimicrobial drug treatments for TB. 

As TB is caused by Mycobacterium tuberculosis, of the same bacterium family as Mycobacterium ulcerans that causes Buruli ulcer, A/Prof approached Swiss Tropical and Public Health Institute (Swiss TPH) to collaborate on researching the effectiveness of Q203 and has proved it is highly effective against Buruli ulcer.

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A/Prof Pethe has been researching on antimicrobial drug treatments for TB

One of the Neglected Tropical Diseases (NTD), Buruli ulcer is a flesh-eating disease that is present in at least 33 countries spanning Africa, South America, Asia and the Western Pacific in tropical, subtropical and temperate areas. Australia and Japan are both classified as endemic areas. It is debilitating and disfiguring, and gives rise to stigma. 

The disease is not easy to treat as it is immune to normal antibiotics.  Traditionally, wide surgical excision of the skin lesions is carried out and since 2004, the World Health Organisation (WHO) has recommended an antibiotic combination of rifampicin and streptomycin. The antibiotic treatment has severe side effects though, with 20% suffering from hearing loss.
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Histopathology figures from the study: the staining is a Ziehl-Neelsen/Methylene blue stain. The first picture shows the numerous pink bacilli in footpad tissue. The second picture shows reduced bacilli after treatment. 

“After four years, we have proved that compound Q203 is highly effective against Buruli ulcer, both in vitro and in vivo. Just as how symptoms of the disease could take as long as two years after infection to show up in humans, making tracing the source as well as tracking how it is spread difficult, the bacteria also developed slowly in vitro,” said A/Prof Pethe. “It is 100% better than the current drug treatment available, which is very harsh, and every required oral dose is lower as well.” 

The compound Q203, which was assigned the non-proprietary name ‘telacebec’ in June 2018, is currently undergoing phase two clinical trial for TB in South Africa, as it has passed safety requirements. “This means that we could jump straight into testing it on Buruli ulcer patients in phase two,” said A/Prof Pethe.

Q203 when used at very low dose (0.5mg/kg) is at least as good as the combination of rifampicin (10mg/kg) and streptomycin (150mg/kg) in animal tests. Due to its high stability in biological fluids, only intermittent dosing is required – perhaps once a week, which is not the case with rifampicin. This would make a simpler regimen possible.
 
The concept may also apply to Mycobacterium leprae, the bacterium that causes leprosy, which is highly endemic in the Asia region. A/Prof Pethe revealed that NTU will be looking to repurpose Q203 for research into treating leprosy – India accounts for 60% of new cases every year while Indonesia is in the top three countries with incidences of this disease.