Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria

被引：122

作者：

Macielag, MJ ^{[1
]}

Demers, JP ^{[1
]}

Fraga-Spano, SA ^{[1
]}

Hlasta, DJ ^{[1
]}

Johnson, SG ^{[1
]}

Kanojia, RM ^{[1
]}

Russel, RK ^{[1
]}

Sui, ZH ^{[1
]}

Weidner-Wells, MA ^{[1
]}

Werblood, H ^{[1
]}

Foleno, BD ^{[1
]}

Goldschmidt, RM ^{[1
]}

Loeloff, MJ ^{[1
]}

Webb, GC ^{[1
]}

Barrett, JF ^{[1
]}

机构：

[1] RW Johnson Pharmaceut Res Inst, Raritan, NJ 08869 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 16期

关键词：

D O I：

10.1021/jm9803572

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/SpoOF, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2,3-dihydroxy-benzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC(50)s of 2.8 and 6.3 mu M, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).

引用

页码：2939 / 2945

页数：7

共 50 条

[31] The mechanism of action of inhibitors of bacterial two-component signal transduction systems
Stephenson, K
Yamaguchi, Y
Hoch, JA
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (49) : 38900 - 38904
[32] Magnetoresistance in Two-Component Systems
Alekseev, P. S.
Dmitriev, A. P.
Gornyi, I. V.
Kachorovskii, V. Yu.
Narozhny, B. N.
Schuett, M.
Titov, M.
[J]. PHYSICAL REVIEW LETTERS, 2015, 114 (15)
[33] Conductivity of two-component systems
deKuijper, A
Sandor, RKJ
Hofman, JP
deWaal, JA
[J]. GEOPHYSICS, 1996, 61 (01) : 162 - 168
[34] Evolutionary Analysis and Lateral Gene Transfer of Two-Component Regulatory Systems Associated with Heavy-Metal Tolerance in Bacteria
Juan L. Bouzat
Matthew J. Hoostal
[J]. Journal of Molecular Evolution, 2013, 76 : 267 - 279
[35] Flocculation with two-component systems
Petzold, G
Buchhammer, HM
Lunkwitz, K
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1996, 212 : 54 - COLL
[36] Evolutionary Analysis and Lateral Gene Transfer of Two-Component Regulatory Systems Associated with Heavy-Metal Tolerance in Bacteria
Bouzat, Juan L.
Hoostal, Matthew J.
[J]. JOURNAL OF MOLECULAR EVOLUTION, 2013, 76 (05) : 267 - 279
[37] An intimate link: two-component signal transduction systems and metal transport systems in bacteria
Singh, Kamna
Senadheera, Dilani B.
Cvitkovitch, Dennis G.
[J]. FUTURE MICROBIOLOGY, 2014, 9 (11) : 1283 - 1293
[38] Streptococcus pneumoniae two-component regulatory systems: The interplay of the pneumococcus with its environment
Gomez-Mejia, Alejandro
Gamez, Gustavo
Hammerschmidt, Sven
[J]. INTERNATIONAL JOURNAL OF MEDICAL MICROBIOLOGY, 2018, 308 (06) : 722 - 737
[39] A connector of two-component regulatory systems promotes signal amplification and persistence of expression
Kato, Akinori
Mitrophanov, Alexander Y.
Groisman, Eduardo A.
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (29) : 12063 - 12068
[40] Comprehensive DNA microarray analysis of Bacillus subtilis two-component regulatory systems
Kobayashi, K
Ogura, M
Yamaguchi, H
Yoshida, KI
Ogasawara, N
Tanaka, T
Fujita, Y
[J]. JOURNAL OF BACTERIOLOGY, 2001, 183 (24) : 7365 - 7370

← 1 2 3 4 5 →