Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 7, Pages 3126-3139Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm500131s
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Funding
- United States Public Health Service (National Institutes of Health) [GM065307, CA158191, HL016101, AI049151]
- National Basic Research Program of China [2011CB710800, 2011CBA00805]
- National Research Foundation of Korea (NRF)
- Korean government (MSIP) [2007-00559]
- Gyeonggi-do [K204EA000001-09E0100- 00110]
- KISTI
- NIH Director's New Innovator Award Program [DP2 OD008463]
- European Community [260872]
- Fondation Jacqueline Beytout
- American Heart Association, Midwest Affiliate [13PRE14510056]
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We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.
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