Antimalarial and antituberculosis substances from Streptomyces sp. BCC26924

Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action

“…[2] It could be shown that the spiroindolonesexert their antiplasmodial activity by perturbation of intracellularN a + levels. [5] Both biological activities were recently also reported for cyclomarin C. [6] We have previously described ClpC1, the regulatory subunit of the ClpP protease as the molecular target of 1 in Mycobacterium tuberculosis (Mtb). [3] As econd potent hit, the fungal isocoumarin compound cladosporin, was further investigated, and the target could be elucidated as the lysyl-tRNA-synthetase by yeast chemogenomic profiling.…”

“…Cyclomarin not only kills Plasmodia,b ut also has ap otent antibacterial activity againstm ycobacteria. [5] Both biological activities were recently also reported for cyclomarin C. [6] We have previously described ClpC1, the regulatory subunit of the ClpP protease as the molecular target of 1 in Mycobacterium tuberculosis (Mtb). [5] ClpC1 wasi dentifiedb yac hemical proteomics approach by use of acyclomarin derivative covalently coupled to ar esin.…”

“…[6] In order to verify ac onservede nzymatic activity for PfA-p3Aase as an A3pA hydrolase and to establisha ne xperimental system for validation of cyclomarin Aa sa ni nhibitor of the enzymatica ctivity of PfAp3Aase in vitro, we expressed three diadenosine polyphosphate hydrolases in E. coli and established enzymatic assays with use of al uminescence readout.I na ddition to the plasmodial and human A3pA hydrolases, we included PFE1035c (PfAp4Aase), which converts Ap4A into ATPa nd AMP.P fAp4Aase has recently been proposed as ap otential antimalaria targeta nd was included in this study as ac ontrol. Its human orthologue hFHIT (human fragile histidinet riad) hydrolyses P(1)-P(3)-bis(5'-adenosyl) triphosphate( Ap3A) to yield AMP and ADP.hFHIT has been implicated as atumour suppressor,a nd aberrant expression has been associated with a number of tumours.…”

“…Its human orthologue hFHIT (human fragile histidinet riad) hydrolyses P(1)-P(3)-bis(5'-adenosyl) triphosphate( Ap3A) to yield AMP and ADP.hFHIT has been implicated as atumour suppressor,a nd aberrant expression has been associated with a number of tumours. [6] In order to verify ac onservede nzymatic activity for PfA-p3Aase as an A3pA hydrolase and to establisha ne xperimental system for validation of cyclomarin Aa sa ni nhibitor of the enzymatica ctivity of PfAp3Aase in vitro, we expressed three diadenosine polyphosphate hydrolases in E. coli and established enzymatic assays with use of al uminescence readout.I na ddition to the plasmodial and human A3pA hydrolases, we included PFE1035c (PfAp4Aase), which converts Ap4A into ATPa nd AMP.P fAp4Aase has recently been proposed as ap otential antimalaria targeta nd was included in this study as ac ontrol. [8] Indeed, we observed A3pA hydrolase activity for recombinant PfAp3Aase in vitro:t he Michaelis-Menten constant (K m )w as determined for the enzyme PfAp3Aase with the preferred substrate Ap3A.…”

Total Synthesis of Carbazomycins A and B

“…Carbazomycin B is also active against malaria. 10,11) Therefore, carbazomycins have been receiving considerable attention, and there have been several reports on their total synthesis. [12][13][14][15][16][17][18][19][20][21][22][23] In the synthesis of these compounds, the methods used to construct the fully substituted benzene ring in their structure have been the main subject of synthetic strategies, because it is generally difficult to construct a fully substituted benzene ring from benzene derivatives by aromatic substitution and/or cross-coupling strategies due to a shortage of reliable methods for installing a functional group at the desired position.…”