Lassomycin, a Ribosomally Synthesized Cyclic Peptide, Kills Mycobacterium tuberculosis by Targeting the ATP-Dependent Protease ClpC1P1P2

Chemistry & biology (Impact Factor: 6.65). 03/2014; 21(4). DOI: 10.1016/j.chembiol.2014.01.014
Source: PubMed


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.

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    • "ClpC1 0.42–1.57 Gavrish et al., 2014 "
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    ABSTRACT: Tuberculosis (TB) is a recurring threat to contemporary civilization. It affects not only those within developing countries, but has also appeared again in places where it was once considered eradicated. TB co-infection in patients infected by HIV is, at the time of writing, the most common cause of death. In the field of searching for new antimycobacterial drug leads, compounds of natural origin still remain a promising source. The review is intended to gather information about natural products (metabolites of plants, fungi, bacteria, and marine sponges) that show activity against mycobacterial enzymes. Here, natural metabolites are presented as being inhibitors/activators of the mycobacterial enzymes involved in mycobacterial growth in vitro (ClpC1, ClpP, MurE ligase, mycothiol S-conjugate amidase, β-ketoacyl-ACP synthase, InhA) and in vivo, as regards the host cell (PtpB). Each enzyme is briefly described so as to generate an understanding of its role in mycobacterial growth and engender a perception of the mechanism of action of the studied natural compounds. Furthermore, after the introduction of the enzyme, its inhibitors are listed and exactly characterized.
    No preview · Article · Oct 2015 · Chemistry & biology
    • "Therefore, alternatives to treat MDR strains are desperate in need. There are some promising compounds in the pipeline (Ling et al. 2015; Gavrish et al. 2014; Roche 2015), but it can be assumed that these substances will most likely not meet the public health needs (Freire-Moran et al. 2011). There is a plethora of ways how bacteria can become resistant. "
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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). "
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    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.
    Full-text · Article · Sep 2014 · Chemistry & Biology
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