The cyclic peptide ecumicin targeting CLpC1 is active against Mycobacterium tuberculosis in vivo

Wei Gao, Jin Yong Kim, Jeffrey R. Anderson, Tatos Akopian, Seungpyo Hong, Ying Yu Jin, Olga Kandror, Jong Woo Kim, In Ae Lee, Sun Young Lee, James B. McAlpine, Surafel Mulugeta, Suhair Sunoqrot, Yuehong Wang, Seung Hwan Yang, Tae Mi Yoon, Alfred L. Goldberg, Guido F. Pauli, Joo Won Suh, Scott G. Franzblau & 1 others Sanghyun Cho

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)880-889
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume59
Issue number2
DOIs
Publication statusPublished - 2015 Feb 1

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Cyclic Peptides
Mycobacterium tuberculosis
Pharmaceutical Preparations
Adenosine Triphosphatases
Multidrug-Resistant Tuberculosis
Lung
Actinobacteria
ecumicin
Proteolysis
Tuberculosis
Peptide Hydrolases
Body Weight
Genome
Growth

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Gao, Wei ; Kim, Jin Yong ; Anderson, Jeffrey R. ; Akopian, Tatos ; Hong, Seungpyo ; Jin, Ying Yu ; Kandror, Olga ; Kim, Jong Woo ; Lee, In Ae ; Lee, Sun Young ; McAlpine, James B. ; Mulugeta, Surafel ; Sunoqrot, Suhair ; Wang, Yuehong ; Yang, Seung Hwan ; Yoon, Tae Mi ; Goldberg, Alfred L. ; Pauli, Guido F. ; Suh, Joo Won ; Franzblau, Scott G. ; Cho, Sanghyun. / The cyclic peptide ecumicin targeting CLpC1 is active against Mycobacterium tuberculosis in vivo. In: Antimicrobial Agents and Chemotherapy. 2015 ; Vol. 59, No. 2. pp. 880-889.
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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.",
author = "Wei Gao and Kim, {Jin Yong} and Anderson, {Jeffrey R.} and Tatos Akopian and Seungpyo Hong and Jin, {Ying Yu} and Olga Kandror and Kim, {Jong Woo} and Lee, {In Ae} and Lee, {Sun Young} and McAlpine, {James B.} and Surafel Mulugeta and Suhair Sunoqrot and Yuehong Wang and Yang, {Seung Hwan} and Yoon, {Tae Mi} and Goldberg, {Alfred L.} and Pauli, {Guido F.} and Suh, {Joo Won} and Franzblau, {Scott G.} and Sanghyun Cho",
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Gao, W, Kim, JY, Anderson, JR, Akopian, T, Hong, S, Jin, YY, Kandror, O, Kim, JW, Lee, IA, Lee, SY, McAlpine, JB, Mulugeta, S, Sunoqrot, S, Wang, Y, Yang, SH, Yoon, TM, Goldberg, AL, Pauli, GF, Suh, JW, Franzblau, SG & Cho, S 2015, 'The cyclic peptide ecumicin targeting CLpC1 is active against Mycobacterium tuberculosis in vivo', Antimicrobial Agents and Chemotherapy, vol. 59, no. 2, pp. 880-889. https://doi.org/10.1128/AAC.04054-14

The cyclic peptide ecumicin targeting CLpC1 is active against Mycobacterium tuberculosis in vivo. / Gao, Wei; Kim, Jin Yong; Anderson, Jeffrey R.; Akopian, Tatos; Hong, Seungpyo; Jin, Ying Yu; Kandror, Olga; Kim, Jong Woo; Lee, In Ae; Lee, Sun Young; McAlpine, James B.; Mulugeta, Surafel; Sunoqrot, Suhair; Wang, Yuehong; Yang, Seung Hwan; Yoon, Tae Mi; Goldberg, Alfred L.; Pauli, Guido F.; Suh, Joo Won; Franzblau, Scott G.; Cho, Sanghyun.

In: Antimicrobial Agents and Chemotherapy, Vol. 59, No. 2, 01.02.2015, p. 880-889.

Research output: Contribution to journalArticle

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AU - Jin, Ying Yu

AU - Kandror, Olga

AU - Kim, Jong Woo

AU - Lee, In Ae

AU - Lee, Sun Young

AU - McAlpine, James B.

AU - Mulugeta, Surafel

AU - Sunoqrot, Suhair

AU - Wang, Yuehong

AU - Yang, Seung Hwan

AU - Yoon, Tae Mi

AU - Goldberg, Alfred L.

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AU - Franzblau, Scott G.

AU - Cho, Sanghyun

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N2 - 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.

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