title: The cyclic peptide ecumicin targeting ClpC1 is active against Mycobacterium tuberculosis in vivo.
abstract: Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action. A high-throughput screening campaign of >65,000 actinomycete extracts for inhibition of Mycobacterium tuberculosis viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against M. tuberculosis in vitro, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. The subcutaneous administration to mice of ecumicin in a micellar formulation at 20 mg/kg body weight resulted in plasma and lung exposures exceeding the MIC. Complete inhibition of M. tuberculosis growth in the lungs of mice was achieved following 12 doses at 20 or 32 mg/kg. Genome mining of lab-generated, spontaneous ecumicin-resistant M. tuberculosis strains identified the ClpC1 ATPase complex as the putative target, and this was confirmed by a drug affinity response test. ClpC1 functions in protein breakdown with the ClpP1P2 protease complex. Ecumicin markedly enhanced the ATPase activity of wild-type (WT) ClpC1 but prevented activation of proteolysis by ClpC1. Less stimulation was observed with ClpC1 from ecumicin-resistant mutants. Thus, ClpC1 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development.
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: Division of Bioscience and Bioinformatics, College of Natural Science, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Anderson
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tatos
authors.initials: T
authors.lastname: Akopian
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Seungpyo
authors.initials: S
authors.lastname: Hong
authors.affiliation: Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Jin
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Kandror
authors.affiliation: B&C Biopharm, AICT, Yeongtong-gu, Suwon, Gyeonggi-Do, South Korea.
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: In-Ae
authors.initials: IA
authors.lastname: Lee
authors.affiliation: Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: McAlpine
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Suhair
authors.initials: S
authors.lastname: Sunoqrot
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Division of Bioscience and Bioinformatics, College of Natural Science, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea.
authors.forename: Tae-Mi
authors.initials: TM
authors.lastname: Yoon
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Guido F
authors.initials: GF
authors.lastname: Pauli
authors.affiliation: Division of Bioscience and Bioinformatics, College of Natural Science, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea Center for Nutraceutical and Pharmaceutical Materials, Myongji University, Cheoin-gu, Yongin, Gyeonggi-Do, South Korea sgf@uic.edu jwsuh@mju.ac.kr.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Suh
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA sgf@uic.edu jwsuh@mju.ac.kr.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Sanghyun
authors.initials: S
authors.lastname: Cho
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018938:Caco-2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D010456:Peptides, Cyclic