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.
Highlights
Drug-resistant tuberculosis (TB) has lent urgency to finding new drug leads with novel modes of action
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, Bennett’s medium, and dextrinyeast-corn steep liquor (DYC) medium
Ninety of the initial hits were profiled for activity against: mammalian cells (Vero cells, 50% inhibitory concentration [IC50]), nonreplicating M. tuberculosis [15], isogenic M. tuberculosis strains that are resistant to SM, RMP, and CS, and M. smegmatis, S. aureus, E. coli, and C. albicans
Summary
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. 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 is a valid drug target against M. tuberculosis, and ecumicin may serve as a lead compound for anti-TB drug development. 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 [1,2,3,4,5]. 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
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