S16
Ecumicin as a novel anti-tuberculosis drug
Tuesday, January 13, 2015: 8:55 AM
California Ballroom AB
Joo-Won Suh1, Jin-Yong Kim2, Wei Gao3, Ying-Yu Jin4, Sang-Hyun Cho5, Alfred Goldberg6, Guido Pauli7, Hanki Lee4 and Scott Franzblau5, (1)Division of Bioscience and Bioinformatics/Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Yongin, (2)Division of Bioscience and Bioinformatics, Myongji University, Yongin, (3)Department of Medicinal Chemistry and Pharmacognosy/Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, IL, (4)Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Yongin, (5)Institute for Tuberculosis Research, University of Illinois at Chicago, Chicago, IL, (6)Department of Cell Biology, Harvard Medical School, Boston, MA, (7)Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL
Tuberculosis (TB) is an infectious disease caused by
Mycobacterium tuberculosis (
Mtb), which cause high mortality rate despite enormous efforts to treat TB. Recently, occurrence of multidrug (MDR) and extensively drug resistant (XDR)
Mtb makes treatment of TB by existing TB drugs harder. Besides, existing TB drugs are often less effective against non-replicating
Mtb that potentially cause TB. Therefore, new TB drugs require efficacy against MDR and XDR as well as non-replicating
Mtb.
In order to address these issues, we screened for anti-TB agents by MABA and LORA from extract library from actinomycete, which are known to be fascinating natural product producers. We selected the extract showing potent anti-Mtb activity and verified that the actinomycetes producing anti-Mtb agent is a novel Nonomuraea species. Based on bioassay, we purified a compound designated H14 and identified that it was a new macrocyclic peptide consisting of 13 amino acids. H14 showed superior anti-Mtb activity against MDR, XDR, and non-replicating strains of Mtb, compared to three first line TB drugs. Moreover, in pharmacokinetic study in mouse, H14 showed good PK that moves to lung, where TB causes lesions. Through target ID study, we discovered that the mode of action of H14 is the acceleration of ATP hydrolysis by its selective target ClpP1/P2 and interferes in protein degradation by related ClpP1/P2.
We demonstrated that H14 is a novel anti-tuberculosis drug candidate that can treat TB with mode of action different from existing TB drugs.
