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1.
Science ; 348(6239): 1106-12, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-26045430

ABSTRACT

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Molecular Targeted Therapy , Mycobacterium tuberculosis/drug effects , Peptides, Cyclic/pharmacology , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Cell Line, Tumor , Crystallography, X-Ray , DNA-Directed DNA Polymerase , Disease Models, Animal , Drug Design , Humans , Mice , Microbial Sensitivity Tests , Molecular Sequence Data , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/enzymology , Mycobacterium tuberculosis/enzymology , Peptides, Cyclic/chemistry , Peptides, Cyclic/therapeutic use , Protein Structure, Secondary , Streptomyces/chemistry , Streptomyces/drug effects , Streptomyces/metabolism , Tuberculosis, Multidrug-Resistant/microbiology
2.
J Pharmacol Exp Ther ; 301(1): 322-32, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11907190

ABSTRACT

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.


Subject(s)
Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Thiazoles/pharmacology , Acetylcholine/metabolism , Adrenocorticotropic Hormone/metabolism , Animals , Brain Chemistry/drug effects , CHO Cells , Cell Membrane/drug effects , Cell Membrane/metabolism , Cricetinae , Cyclic AMP/biosynthesis , Female , Gerbillinae , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Male , Mice , Microdialysis , Rats , Receptors, Corticotropin-Releasing Hormone/drug effects , Receptors, Corticotropin-Releasing Hormone/metabolism , Stress, Psychological/metabolism
3.
J Pharmacol Exp Ther ; 301(1): 333-45, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11907191

ABSTRACT

The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.


Subject(s)
Behavior, Animal/drug effects , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Stress, Psychological/drug therapy , Thiazoles/pharmacology , Animals , Antidepressive Agents/therapeutic use , Anxiety/drug therapy , Anxiety/psychology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Conflict, Psychological , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Fear/drug effects , Hypothermia/prevention & control , Male , Memory/drug effects , Mice , Motor Activity/drug effects , Norepinephrine/metabolism , Punishment , Rats , Rats, Sprague-Dawley , Rats, Wistar , Social Isolation/psychology , Stress, Psychological/physiopathology , Swimming/psychology , Vocalization, Animal/drug effects
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