The Natural Product Cyclomarin Kills Mycobacterium Tuberculosis by Targeting the ClpC1 Subunit of the Caseinolytic Protease

Schmitt, E.; Riwanto, Meliana; Sambandamurthy, Vasan K.; Roggo, Silvio; Miault, Charlotte; Zwingelstein, Christian; Krastel, Philipp; Noble, Christian G.; Beer, David; Rao, Srinivasa P. S.; Au, Melvin; Niyomrattanakit, Pornwaratt; Lim, Viviam; Zheng, Jun; Jeffery, Douglas A.; Pethe, Kévin; Camacho, Luis R.

doi:10.1002/anie.201101740

Cited by 161 publications

(150 citation statements)

References 20 publications

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“…However, in M. tuberculosis, ADEPs appear to act primarily by blocking the interaction of ClpP1P2 with its regulatory ATPases. Enhancement of ClpC1-mediated proteolysis has also been proposed as the mode of action of the antibiotic cyclomarin, which also binds to ClpC1 (39,40). An uncoupling mechanism similar to that observed here has recently been demonstrated for lassomycin, another M. tuberculosisspecific cyclic peptide antibiotic that also targets ClpC1 (41).…”

Section: Discussionsupporting

confidence: 70%

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Gao

Kim

Anderson

et al. 2015

Antimicrob Agents Chemother

162

224

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Mycobacterium tuberculosis is the cause of one of the most deadly diseases of mankind, and despite the availability of effective treatments, tuberculosis (TB) remains a major public health threat. The difficult challenges in treating multiple-drugresistant (MDR) and extensively drug-resistant (XDR) TB and the importance of shortening the duration of treatment to improve patients' compliance make the discovery of new anti-TB drugs imperative (1-5). Attempts to discover new TB drugs and targets via large-scale screening against intact mycobacteria have largely been confined to synthetic compound libraries and to date have yielded only one new clinical TB drug, the diarylquinoline bedaquiline (6, 7). Although very potent, to be of maximum benefit, bedaquiline, a diarylquinoline, and nitroimidazoles (8) require new companion drugs to be used in a multidrug regimen.While the intensive search for antibiotics from soil microorganisms in the mid-20th century yielded several clinically useful TB drugs, the pathogenic nature of M. tuberculosis and its extremely slow growth rate did not allow classical agar diffusion tests and excluded M. tuberculosis from the initial target panel. The discovery of TB drugs of natural origin at that time therefore relied upon the detection of activity against nonmycobacteria in agar diffusion assays followed by bioassay-guided isolation of the active principle, again using nonmycobacteria. Activity against M. tuberculosis was only assessed once the active principle was purified.Because M. tuberculosis is uniquely susceptible to a number of antimicrobial agents, a high-throughput screening (HTS) of actinomycete extracts directly against the virulent H37Rv strain was conducted, and this campaign revealed selective anti-TB peptides produced by a genetically distinct Nonomuraea species, strain MJM5123. Here, we describe the activity profile of ecumicin, its efficacy in infected mice, the identification of its molecular target, and the elucidation of its unusual mechanism of action. MATERIALS AND METHODSHigh-throughput screening. Approximately 7,000 actinomycete cultures isolated from Korea, China, Nepal, the Philippines, Vietnam, Antarctica, and the Arctic Circle and maintained at Myongji University, South Korea, were fermented in 20-ml cultures in glucose-soybean starch (GSS) medium (rich medium), Bennett's medium (normal medium), and dextrinyeast-corn steep liquor (DYC) medium (minimal medium) (see Table S1 in the supplemental material). The mycelia and culture medium supernatants were separated and extracted with methanol and ethyl acetate, respectively. Nine extracts were thus generated from each microbial isolate.

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Section: Discussionsupporting

confidence: 70%

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

Gao

Kim

Anderson

et al. 2015

Antimicrob Agents Chemother

162

224

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“…The antibodies were affinity-purified by using specific peptides as ligands. Antibody against ClpC1 (14) was used as an internal control.…”

Section: Methodsmentioning

confidence: 99%

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

Zheng

Rubín

Bifani

et al. 2013

Journal of Biological Chemistry

Self Cite

177

115

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Background: PAS is an antimycobacterial whose mechanism(s) of action remains elusive. Results: PAS is incorporated into the folate pathway by DHPS-DHFS, generating an anti-metabolite. DHFS and RibD are associated with PAS resistance. Conclusion: Hydroxyl dihydrofolate inhibits DHFR. folC and ribD are drug target genes for identification of clinical PAS resistance. Significance: Metabolite analog incorporation into essential biosynthetic pathways is promising for developing antibacterials.

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“…70 Although it was described in 1999 as a potent anti-inflammatory agent with cytotoxicity against cancer cells, it was not until 2011 that activity against M. tuberculosis was discovered during a natural product whole-cell screen. 71 In a first attempt to identify cymA's molecular target, a reverse genomics approach was taken. However, after no spontaneous resistant M. tuberculosis mutants could be recovered, affinity chromatography was instead used to show that cymA targets ClpC1 with high specificity.…”

Section: Aaa+ Atpase Uncouplers As Therapeuticsmentioning

confidence: 99%

“…In contrast to ecumicin and lassomycin, cymA has been suggested to increase protein degradation, as demonstrated by a decrease in LeuAspAsp tripeptide-tagged green fluorescent protein fluorescence targeted to ClpC1 on incubation with cymA. 71 However, it is possible that this decrease in fluorescence is the result of green fluorescent protein unfolding by ClpC1 rather than degradation and cymA may therefore have the same uncoupling mechanism as ecumicin and lassomycin. Several questions remain unanswered about the mechanism of action of these drugs, including their effects on protein unfolding and how ATPase activity is stimulated and proteolysis inhibited, for example, by inhibiting interaction with ClpP1P2.…”

Section: Aaa+ Atpase Uncouplers As Therapeuticsmentioning

confidence: 99%

Bacterial proteases, untapped antimicrobial drug targets

2016

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Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

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The Natural Product Cyclomarin Kills Mycobacterium Tuberculosis by Targeting the ClpC1 Subunit of the Caseinolytic Protease

Cited by 161 publications

References 20 publications

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

The Cyclic Peptide Ecumicin Targeting ClpC1 Is Active against Mycobacterium tuberculosis In Vivo

para-Aminosalicylic Acid Is a Prodrug Targeting Dihydrofolate Reductase in Mycobacterium tuberculosis

Bacterial proteases, untapped antimicrobial drug targets

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