TY - JOUR
T1 - Multitarget drug discovery for tuberculosis and other infectious diseases
AU - Li, Kai
AU - Schurig-Briccio, Lici A.
AU - Feng, Xinxin
AU - Upadhyay, Ashutosh
AU - Pujari, Venugopal
AU - Lechartier, Benoit
AU - Fontes, Fabio L.
AU - Yang, Hongliang
AU - Rao, Guodong
AU - Zhu, Wei
AU - Gulati, Anmol
AU - No, Joo Hwan
AU - Cintra, Giovana
AU - Bogue, Shannon
AU - Liu, Yi Liang
AU - Molohon, Katie
AU - Orlean, Peter
AU - Mitchell, Douglas A.
AU - Freitas-Junior, Lucio
AU - Ren, Feifei
AU - Sun, Hong
AU - Jiang, Tong
AU - Li, Yujie
AU - Guo, Rey Ting
AU - Cole, Stewart T.
AU - Gennis, Robert B.
AU - Crick, Dean C.
AU - Oldfield, Eric
PY - 2014/4/10
Y1 - 2014/4/10
N2 - 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.
AB - 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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U2 - 10.1021/jm500131s
DO - 10.1021/jm500131s
M3 - Review article
C2 - 24568559
AN - SCOPUS:84898408111
SN - 0022-2623
VL - 57
SP - 3126
EP - 3129
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -