Lassomycin, a Ribosomally Synthesized Cyclic Peptide, Kills Mycobacterium tuberculosis by Targeting the ATP-Dependent Protease ClpC1P1P2
ABSTRACT Languishing antibiotic discovery and flourishing antibiotic resistance have prompted the development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against Mycobacterium tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells. Lassomycin is a highly basic, ribosomally encoded cyclic peptide with an unusual structural fold that only partially resembles that of other lasso peptides. We show that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2-catalyzed protein breakdown, which is essential for viability of mycobacteria. This mechanism, uncoupling ATPase from proteolytic activity, accounts for the bactericidal activity of lassomycin.
- SourceAvailable from: Aleksandr Milshteyn
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- "The same group extended this simulation to culture rarely accessed aerobic and anaerobic species from subsurface sediment (Bollmann et al., 2010), and a commercial venture founded on these approaches has reported a number of novel metabolites in the patent literature, including two novel glycosylated macrolactam antibiotics NOVO3 and NOVO4 (3) with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) with minimal in vitro toxicity to mammalian cells (Lewis et al., 2009; Peoples et al., 2011). Furthermore, by focusing screening efforts on identifying small molecules with a narrow range of activity against a specific pathogen , the collection of extracts from in situ and prolonged cultivation studies (up to 18 months; Buerger et al., 2012) resulted in the identification of lassomycin, a ribosomal cyclic peptide with potent activity against Mycobacterium tuberculosis, from the extract of Lentzea kentuckyensis (Gavrish et al., 2014). Other related techniques that have been used to culture isolated bacteria in simulated native environments in the laboratory include culturing on supporting membranes suspended on a soil slurry (Ferrari et al., 2005) and embedding single cells in agarose microdroplets and culturing them in flowing seawater (Zengler et al., 2002) or directly on living coral (Ben-Dov et al., 2009). "
ABSTRACT: Microbial-derived natural products provide the foundation for most of the chemotherapeutic arsenal available to contemporary medicine. In the face of a dwindling pipeline of new lead structures identified by traditional culturing techniques and an increasing need for new therapeutics, surveys of microbial biosynthetic diversity across environmental metabiomes have revealed enormous reservoirs of as yet untapped natural products chemistry. In this review, we touch on the historical context of microbial natural product discovery and discuss innovations and technological advances that are facilitating culture-dependent and culture-independent access to new chemistry from environmental microbiomes with the goal of reinvigorating the small molecule therapeutics discovery pipeline. We highlight the successful strategies that have emerged and some of the challenges that must be overcome to enable the development of high-throughput methods for natural product discovery from complex microbial communities.Chemistry & Biology 09/2014; 21(9):1211-1223. DOI:10.1016/j.chembiol.2014.08.006 · 6.65 Impact Factor
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- "The described in vitro system will be very useful for understanding the molecular mechanism and activity of the recently discovered antimicrobial compounds cyclomarin or lassomycin (Schmitt et al., 2011; Gavrish et al., 2014). For example, it is unclear how their interaction with the N-terminal domain of ClpC1 might influence the substrate selection of ClpC1P1P2 and how the lassomycin mediated induction of the ClpC1 ATPase could influence substrate selection and degradation (Vasudevan et al., 2013; Gavrish et al., 2014). The results of Schmitz and Sauer also suggest that a concurrent activation of the essential ClpP1P2 system by N-blocked dipeptides or ADEP might make it vulnerable for specific ClpP inhibitors (Gersch et al., 2013). "
ABSTRACT: Hsp100/Clp protease complexes are molecular machines important for cellular protein homeostasis and are concurrently embedded in the control of various signal transduction networks by regulatory proteolysis. In Mycobacteria, the genes encoding the components of these Hsp100/Clp protease complexes are essential for growth and were identified as targets for antibiotics, with a new antimicrobial mechanism, that are active on slow growing or even dormant cells. In this issue, Schmitz and Sauer report the biochemical characterization of mycobacterial Hsp100/Clp protease complexes actively degrading folded substrate proteins. Their results suggest an unusual activation mechanism for this protease complex and will set the stage for further mechanistic studies of antibiotics acting on this new cellular target.Molecular Microbiology 06/2014; 93(4). DOI:10.1111/mmi.12696 · 4.42 Impact Factor
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ABSTRACT: Controlled proteolysis is key to bacterial viability. In this issue of Chemistry & Biology, Gavrish and colleagues characterize a natural product, lassomycin, targeting the Mycobacterium tuberculosis caseinolytic (Clp) protease. Unusually, lassomycin activates ClpC1, inducing ATPase activity and decoupling it from proteolysis.Chemistry & biology 04/2014; 21(4):437-8. DOI:10.1016/j.chembiol.2014.04.002 · 6.65 Impact Factor