Cyclomarin A

Cyclomarin A binds to a conserved hydrophobic pocket on Mycobacterium tuberculosis ClpC1_NTD, which serves as the receptor site for misfolded proteins^[1].
Cyclomarin A (0.01-25 μM) potently activates the ATPase activity of the chimeric protein N_Mtb-ClpC, with a K_0.5 of 0.3 μM; it partially activates Sa ClpC-Y80F, but has no effect on wild-type Sa ClpC^[4].
Cyclomarin A (0.1-25 μM) enables N_Mtb-ClpC/Sa ClpP to degrade FITC-casein in an adaptor-independent manner, with a half-maximal activity concentration of 0.13 μM; this agent induces partial degradation of Sa ClpC-Y80F/Sa ClpP, but exerts no effect on wild-type Sa ClpC/Sa ClpP^[4].
Cyclomarin A (10 μM) activates N_Mtb-ClpC/Sa ClpP to degrade unlabeled casein and the native substrate FtsZ, while inhibiting the degradation of MecA by this complex^[4].
Cyclomarin A (10 μM) activates N_Mtb-ClpC/Sa ClpP to degrade the stably folded substrates Casein-YFP and GFP-SsrA, but its unfolding activity is significantly reduced compared with MecA activation^[4].
Cyclomarin A (20 μM) induces the formation of a large, homogeneous 24.2-mer assembly composed of multiple hexamers from N_Mtb-ClpC-DWB, and this assembly interacts with Sa ClpP^[4].
Cyclomarin A (20 μM; 10 min) induces conformational changes in N_Mtb-ClpC, which are highly similar to those induced by MecA, including increased stability of key domains associated with ATP binding and hydrolysis^[4].

Cyclomarin A exhibits moderate cytotoxicity against a variety of cancer cell lines, with an IC₅₀ of ~2.5 μM^[2].

Cyclomarin A selectively inhibits PfAp3Ase of Plasmodium falciparum in the nanomolar concentration range, without inhibiting the human FHIT enzyme^[2].
Cyclomarin A inhibits the growth of the erythrocytic stage of *Plasmodium falciparum* strain NF54, with an IC₅₀ of 40 nM^[3].
Cyclomarin A potently inhibits recombinant *Plasmodium falciparum* PfAp3Aase with an IC₅₀ of 4 nM; it does not inhibit recombinant *Plasmodium falciparum* PfAp4Aase or human hFHIT even at concentrations as high as 10 μM^[3].
Cyclomarin A binds to the central channel of the homodimeric *Plasmodium falciparum* PfAp3Aase, and inhibits enzymatic activity by blocking substrate access to the two binding sites via steric hindrance^[3].
Cyclomarin A (100 μM) specifically binds to *Plasmodium falciparum* PfAp3Aase, which is demonstrated by a binding competition rate of >75% in affinity chromatography experiments^[3].

Cyclomarin A exhibits antibacterial activity against *Mycobacterium tuberculosis* (MTB)^[2].
Cyclomarin A inhibits the growth of *Mycobacterium tuberculosis* with a MIC₅₀ of 0.1 μM by binding to ClpC1 and regulating proteolytic processes^[3].
Cyclomarin A (0.1-10 μM; 24 h) is toxic to *E. coli* cells co-expressing N_Mtb-ClpC and Sa ClpP, reducing cell viability by 1000-fold at a concentration of 10 μM and exerting maximal toxicity at 1 μM, with its mechanism of action being uncontrolled proteolysis of intracellular proteins^[4].
Cyclomarin A (5 μM) binds to purified *Mycobacterium tuberculosis* ClpC2 with a dissociation constant of 2.2 nM, exhibiting a tight 1:1 binding mode, and its affinity is comparable to that for ClpC1 NTD^[5].
Cyclomarin A (at a 1.1-fold molar excess relative to ClpC2_94-252) binds to the C-terminal domain (residues 94-252) of Mycobacterium tuberculosis ClpC2 in an almost identical manner to its binding to ClpC1 NTD, as confirmed by a co-crystal structure with a resolution of 1.43 Å^[5].
Cyclomarin A (150 nM; up to 100 hours) inhibits the growth of Mycobacterium smegmatis ΔclpC2 strain, while wild-type strains and clpC2-complemented strains remain unaffected, indicating that ClpC2 mediates resistance to CymA-induced toxicity through direct binding^[5].
Cyclomarin A (150 nM; 1-8 h) significantly upregulates the expression of ClpC2 protein in *Mycobacterium smegmatis*, and its expression level reaches 84 times that of stably expressed ClpC1 at 8 h post-treatment^[5].
Cyclomarin A (150 nM; 1 h) upregulates the transcription level of clpC2 in *Mycobacterium smegmatis* by 263-fold^[5].
The proteolytic activity of Cyclomarin A (2-20 μM)-stimulated ClpC1P against FITC-casein is dose-dependently inhibited by purified *Mycobacterium tuberculosis* ClpC2, with nearly complete inhibition observed at a ClpC2 concentration of 20 μM^[5].
Cyclomarin A (1 μM; 20 min) inhibits the binding of purified *Mycobacterium tuberculosis* ClpC2 to its own operon DNA^[5].