Study reveals novel hybrid molecules to reverse antimicrobial resistance in TB

Promising drug candidates arising from cross-country collaboration are now premise of patent application

Picture shows the novel hybrid chemical lead for drug development

A Birkbeck-led study has led to the design of novel anti-tuberculosis compounds, offering new avenues in the fight against treatment-resistant strains of the bacterial disease. 

Mycobacterium tuberculosis is a pathogenic bacterium which is responsible for causing tuberculosis (TB), and every year, nearly 9 million healthy individuals get newly infected resulting in 1.5 million deaths. Treatment of the disease involves a harsh course comprising of a cocktail of antibiotics over a period of many months. To complicate matters further, multi-, extensively- and even totally-drug resistant tuberculosis (MDR-, XDR-, TDR-TB) cases make the disease, virtually impossible to treat as most drugs in use today are ineffective against them.

The urgent need for new, shorter therapeutic regimens and new classes of drugs active against these drug-resistant bugs drove a cross-country collaboration among researchers who specialise in chemical synthesis and molecular microbiology. The scientists were based at Birkbeck’s Department of Biological Sciences, King’s College London, University College London, Durham University in the UK (UK-team led by Dr. Sanjib Bhakta and Dr Daniele Castagnolo) and at Siena University in Italy (Italy-team led by Dr Fabrizio Manetti) to develop potential anti-TB drugs.

This inter-disciplinary effort resulted in the exhaustive evaluation of a library of hybrid derivatives of two lead drug candidates for their anti-tubercular properties against MTB and MDR-TB strains. The library of molecules were synthesised based on the common features of the compounds BM212 and SQ109 – both of which generated tremendous interest in the anti-infective drug discovery discipline, as they were found to be potent anti-mycobacterial agents.

The researchers achieved five novel hybrid molecules that showed anti-tubercular activity against MTB at ≤1.0 mg/L, two of which proved to be highly active against MDR-TB clinical isolates as well.

One of the potent anti-tubercular derivatives showed low eukaryotic cell-toxicity, to be a lead candidate for preclinical development. In addition, four compounds showed potent whole-cell drug efflux inhibition in mycobacteria, and thus turning to be prospective multi-drug resistance reversal agents.

These promising drug candidates are now the main premise of a patent application being submitted by UCL Business (UCLB) and more information on these compounds and their biological properties can be found in the latest issue of the peer-reviewed Journal of Medicinal Chemistry.

Dr Bhakta said: “Alarmingly, the antimicrobial resistance is rising and affecting the world health and well-being more than ever before. Our timely international academic coalition in integrating interdisciplinary research has drawn a new hope to tackle the scientific challenge by reversing the tide of antibiotic resistance in treating major infectious diseases”

Find out more

(Image caption: Picture shows the novel hybrid chemical lead for drug development)