Salicylic acid (SA) is a defense hormone required for both local and systemic acquired resistance (SAR) in plants. Pathogen infections induce SA synthesis through up-regulating the expression of Isochorismate Synthase 1 (ICS1), which encodes a key enzyme in SA production. Here we report that both SAR Deficient 1 (SARD1) and CBP60g are key regulators for ICS1 induction and SA synthesis. Whereas knocking out SARD1 compromises basal resistance and SAR, overexpression of SARD1 constitutively activates defense responses. In the sard1-1 cbp60g-1 double mutant, pathogen-induced ICS1 upregulation and SA synthesis are blocked in both local and systemic leaves, resulting in compromised basal resistance and loss of SAR. Electrophoretic mobility shift assays showed that SARD1 and CBP60g represent a plant-specific family of DNA-binding proteins. Both proteins are recruited to the promoter of ICS1 in response to pathogen infections, suggesting that they control SA synthesis by regulating ICS1 at the transcriptional level.

In both plants and animals, nucleotide-binding (NB) domain and leucine-rich repeat (LRR)-containing proteins (NLR) function as sensors of pathogen-derived molecules and trigger immune responses. Although NLR resistance (R) proteins were first reported as plant immune receptors more than 15 years ago, how these proteins activate downstream defense responses is still unclear. Here we report that the Toll-like/interleukin-1 receptor (TIR)-NB-LRR R protein, suppressor of npr1-1, constitutive 1 (SNC1) functions through its associated protein, Topless-related 1 (TPR1). Knocking out TPR1 and its close homologs compromises immunity mediated by SNC1 and several other TIR-NB-LRR-type R proteins, whereas overexpression of TPR1 constitutively activates SNC1-mediated immune responses. TPR1 functions as a transcriptional corepressor and associates with histone deacetylase 19 in vivo. Among the target genes of TPR1 are Defense no Death 1 (DND1) and Defense no Death 2 (DND2), two known negative regulators of immunity that are repressed during pathogen infection, suggesting that TPR1 activates R protein-mediated immune responses through repression of negative regulators.histone deacetylase 19 | plant immunity | Topless | Topless-related 1 P lant resistance (R) proteins play important roles in defense against pathogens. The majority of R proteins contain either a Toll-like/interleukin 1 receptor (TIR) or a coiled coil (CC) domain at their N terminus domain, a central nucleotide-binding (NB) domain, and C-terminal leucine-rich repeats (LRRs). Downstream components for TIR-and CC-NB-LRR R proteins appear to be different. Mutations in enhanced disease susceptibility 1 (EDS1), phytoalexin deficient 4 (PAD4), and senescence-associated gene101 (SAG101) affect the resistance specified by TIR-NB-LRR but not by CC-NB-LRR R proteins (1-3). On the other hand, mutations in non-race-specific disease resistance 1 (NDR1) compromise resistance mediated by CC-NB-LRR but not by TIR-NB-LRR R proteins (1, 4). EDS1, PAD4, and SAG101 encode three related proteins with homology to acyl hydrolases (3,5,6). How these proteins regulate R protein signaling is not clear.Increasing evidence suggests that certain R proteins accumulate in the nucleus and that the nuclear pools of these R proteins are important for the activation of defense responses (7-10). Multiple TIR-NB-LRR R proteins, including nicotiana glutinosa virus resistance protein (N) in tobacco and resistance to Pseudomonas syringae 4 (RPS4) and suppressor of npr1-1, constitutive 1 (SNC1) in Arabidopsis, have been shown to localize to the nucleus, and reduction of the nuclear R protein pool attenuates the activation of downstream defense responses (7-10). These findings are consistent with that the nucleocytoplasmic trafficking machinery is required for R protein-mediated immunity (9,11,12). However, the function of these R proteins in the nucleus and whether they participate directly or indirectly in transcriptional regulation of defense genes is unclear.Despite tremendous progress has been made ...

Existing macrolides have never shown definitive clinical efficacy in tuberculosis. Recent reports suggest that ribosome methylation is involved in macrolide resistance in Mycobacterium tuberculosis, a mechanism that newer macrolides have been designed to overcome in gram-positive bacteria. Therefore, selected macrolides and ketolides (descladinose) with substitutions at positions 9, 11,12, and 6 were assessed for activity against M. tuberculosis, and those with MICs of <4 M were evaluated for cytotoxicity to Vero cells and J774A.1 macrophages. Several compounds with 9-oxime substitutions or aryl substitutions at position 6 or on 11,12 carbamates or carbazates demonstrated submicromolar MICs. For the three macrolide-ketolide pairs, macrolides demonstrated superior activity. Four compounds with low MICs and low cytotoxicity also effected significant reductions in CFU in infected macrophages. Active compounds were assessed for tolerance and the ability to reduce CFU in the lungs of BALB/c mice in an aerosol infection model. A substituted 11,12 carbazate macrolide demonstrated significant dose-dependent inhibition of M. tuberculosis growth in mice, with a 10-to 20-fold reduction of CFU in lung tissue. Structure-activity relationships, some of which are unique to M. tuberculosis, suggest several synthetic directions for further improvement of antituberculosis activity. This class appears promising for yielding a clinically useful agent for tuberculosis.Tuberculosis (TB) has been recognized as a major public health problem worldwide, exacerbated greatly by the human immunodeficiency virus pandemic. The length and complexity of antibiotic therapy for tuberculosis and the emergence of multidrug-resistant strains make a compelling case for the development of new efficacious anti-TB drugs.The development of new members of classes of established antibiotics, such as the macrolides, which already possess many desirable pharmacological properties, is one approach to rapidly add new drugs to the existing anti-TB armamentarium.Although they are antibiotics of choice for several respiratory pathogens and have demonstrated efficacy in other mycobacterioses, such as leprosy (6,15,17) and Mycobacterium avium (14,26,27) infections, the macrolides developed to date have lacked potency against the tubercle bacillus (24). The clinical use of clarithromycin in treating tuberculosis is limited to multiple-drug-resistant cases in which there are few remaining treatment options (21).The current development goal for macrolides has been primarily to overcome ribosome modification and drug efflux, the major mechanisms of resistance to this antibiotic class (22). Methylation of A2058, located in the peptidyl transferase loop of domain V of the 23S rRNA subunit, by specific methylases (erm) decreases macrolide binding affinity, rendering the organisms resistant to macrolides, lincosamides, and streptogramins, known as the MLS B phenotype (28,29). Macrolides in which the cladinose group is replaced with a keto group (ketolides) avoid efflux-med...

A study of intramolecular hydrogen bonding in chloroform for a small combinatorial library of nine triamides with varying connecting chain length has been completed. The starting materials for the triamides are three diacids (succinic, glutaric, and adipic acid) and three amino acids (glycine, beta-alanine, and gamma-aminobutyric acid). The preferences for the head-to-tail type of folding pattern are identified for the smaller triamides (1 and 4). The preference for the head-to-tail folding pattern can be explained by the energetic superiority of an optimal hydrogen bond geometry in which the NH---O bond angle is near linearity. The beta-alanine containing triamides 2, 5, and 8 are resistant to intramolecular hydrogen bonding, especially to nearest neighbor hydrogen bonding. At lower temperatures, triamides 2 and 5 exhibit a small population of head-to-tail type of folding, while triamide 8 shows a significant population of bifurcated conformation. Triamide 6, 7, and 9 prefer bicyclic structures involving nearest neighbor hydrogen bonding. A nine-membered ring is large enough to accommodate a near linear N-H--O bond angle. Entropic effects are probably responsible for the preference of the nine-membered ring over a 12- or a 14-membered ring. The enhancement of hydrogen bonding in triamide 9 is enormous, and both NHs have a very large temperature dependence of chemical shifts (-15 ppb/K and -13.3 ppb/K for the terminal and the internal NH protons, respectively). Using appropriate temperature-dependent lower and upper limits of chemical shifts, a van't Hoff analysis gives the hydrogen bond strength for the terminal NH (DeltaH = -3.1 +/- 0.5 kcal/mol) and for the internal NH (DeltaH = -2.8 +/- 0.5 kcal/mol). The increased hydrogen bond strength is taken as evidence for hydrogen-bonding cooperativity from the two mutually enhanced individual hydrogen bonds. A near linear NH--O bond angle is required for this effect.