Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus [Experimental Therapeutics]

ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis (M. tb) infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act at this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tb through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tb (MIC 0.02 µM) and Mycobacterium abscessus (MIC 0.4 µM). Spontaneously generated mutants resistant to RUFI involved seven unique SNP mutations at three distinct codons within the NTD domain of clpC1 (V13, H77, F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, while having no significant effect on the ATPase activity of ClpC1. This represents a marked difference to ecumicin, which inhibits ClpC1 proteolysis but stimulates the ATPase activity, thereby providing evidence that although these peptides share ClpC1 as macromolecular target, their downstream effects are distinct, likely due to differences in binding.

http://bit.ly/2Ql6yHA