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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, American Society for Microbiology 2015 Antimicrobial Agents and Chemotherapy Vol.59 No.2
<P>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 <I>Mycobacterium tuberculosis</I> viability identified ecumicin, a macrocyclic tridecapeptide that exerts potent, selective bactericidal activity against <I>M. tuberculosis</I> <I>in vitro</I>, including nonreplicating cells. Ecumicin retains activity against isolated multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of <I>M. tuberculosis</I>. 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 <I>M. tuberculosis</I> 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 <I>M. tuberculosis</I> 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 <I>M. tuberculosis</I>, and ecumicin may serve as a lead compound for anti-TB drug development.</P>