Lassomycin - Calbiochem

A highly basic synthetic 16-aminoacid cyclic peptide that displays bactericidal activity against multiple species of growing and dormant mycobacteria, including drug-resistant Mycobacterium tuberculosis (MBC = 1- 4 µg/ml) in a time-dependent manner. Displays only a trivial activity against other bacteria (MIC >50 µg/ml) and mammalian cells (IC₅₀ = 350 µg/ml in NIH 3T3 and HepG2 cells). Acts by reversibly binding to a highly acidic N-terminal region of the ClpC1 ATPase complex (K_d = 410 nM) and stimulates its ATPase activity, but uncouples it from ClpP1P2-dependent proteolysis, a step that is essential for mycobacterium viability. Does not affect other related hexameric AAA ATPases. Displays greater bactericidal potency against M. tuberculosis than rifampicin (Cat. No. 557303).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

A synthetic 16-aa lasso peptide with an N-terminal cyclized 8-aa loop followed by an 8-aa spoke with a C-terminus methyl-ester modification, originally identified in actinomycete Lentzea kentuckyensis sp. and reported to exhibit mycobacterium-selective antibiotic activity against M. avium subsp. paratuberculosis, M. smegmatis, and M. tuberculosis (minimum inhibitory concentration/MIC from 0.78 to 3.1 µg/mL; 0.41 to 1.65 µM), including Mtb strains resistant to isoniazid, rifampicin (Cat. No. 557303), streptomycin (Cat. No. 5711), ethambutol, pyrazinamide, and flouroquinolones, while exhibiting much reduced or little potency toward a panel of 16 actinobacteria (MIC from 12.5 to 50 µg/mL against P. acnes & B. longum; MIC >50 µg/mL against the rest) or cytotoxicity in NIH 3T3 & HepG2 cultures (IC₅₀ = 350 µg/mL). Lassomycin is shown to selectively activate the ATPase activity of Mtb ClpC1 (Kd = 0.41 µM) without affecting other AAA family ATPases, including Mtb ClpX, archaea PAN, murine 26S proteasome, and E coli. ClpA, ClpB, and GroEL, resulting in an inhibition instead of activation of ClpC1 ATPase activity-dependent ClpP1P2 proteolytic activity (by 100% at 10 µM against casein degradation; 100 nM P1P2 + 100 nM C1 + 2 mM ATP), most likely by inducing a ClpC1 conformational change via cooperative binding (Hill coefficient = 2.1) that does not prevent ClpC1 & protein substrate binding, but uncouples ClpC1 from ClpP1P2-mediated protein degradation. Unlike Rifampicin, Lassomycin is effective against not just exponentially growing, but also stationary phase, Mtb cultures.

Cell permeable: yes

Primary Target
ClpC1 ATPase complex

Toxicity: Standard Handling (A)

{cyclic(Gly-Leu-Arg-Arg-Leu-Phe-Ala-Asp)}-Gln-Leu-Val-Gly-Arg-Arg-Asn-Ile-CO₂CH₃

Supplied as a trifluoroacetate salt.

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Gavrish, E., et al. 2014. Chem. Biol.21, 509.

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