Open Labs Fellow/s

Stefan Jackenroll

GSK’s contribution

NA

Project Description

The rise of multi-drug- and extensively-drug-resistant mycobacterial strains increasingly hampers current TB treatments. The development of new drugs is therefore highly sought after.

The DNA-dependent RNA polymerase (RNAP) plays a fundamental role in the transcription cycle and is essential for all living organisms.[1] Bacterial RNAPs differ structurally and functionally from their eukaryotic counterparts and thus represent interesting drug targets.[2] Since the RNAP of Mycobacterium tuberculosis constitutes the target of the natural product analog Rifampicin, it is clinically validated but largely underexploited in TB-drug discovery.[3]

Fidaxomicin is a known RNAP-inhibitor of several gram-positive bacteria which is also named Lipiarmycin A3 or Tiacumicin B.[4] It is clinically applied against Clostridium difficile infections[5] and shows promising in vitro activity against Mycobacterium tuberculosis (MICH37Rv = 0.085-3.1 µg/mL).[6-8] Additionally, Fidaxomicin exhibits good activity against a number of multi-drug-resistant TB strains (see appendix I), no cross-resistance to rifampicin or other front-line TB-drugs and a low frequency of spontaneous resistant mutants ( ̴1 in 108 cells/mL).[8]

With this data in hand, we believe that the natural product Fidaxomicin represents a promising starting point for a TB optimisation programme.

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