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Linsen Li Antony Okumu Sheri Dellos-Nolan Zoe Li Soumendrakrishna Karmahapatra Anthony English Jack C. Yalowich Daniel J. Wozniak Mark J. Mitton-Fry 《Bioorganic & medicinal chemistry letters》2018,28(14):2477-2480
Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1?μg/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs. 相似文献
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Joanna Jeleska Jiyoung Lee Andrew J. Manning Donald J. Wolfgeher Youngjoo Ahn George Walters-Marrah Ivan E. Lopez Lissette Garcia Sheri A. McClerklin Richard W. Michelmore Stephen J. Kron Jean T. Greenberg 《PLoS pathogens》2021,17(11)
The plant pathogen Pseudomonas syringae secretes multiple effectors that modulate plant defenses. Some effectors trigger defenses due to specific recognition by plant immune complexes, whereas others can suppress the resulting immune responses. The HopZ3 effector of P. syringae pv. syringae B728a (PsyB728a) is an acetyltransferase that modifies not only components of plant immune complexes, but also the Psy effectors that activate these complexes. In Arabidopsis, HopZ3 acetylates the host RPM1 complex and the Psy effectors AvrRpm1 and AvrB3. This study focuses on the role of HopZ3 during tomato infection. In Psy-resistant tomato, the main immune complex includes PRF and PTO, a RIPK-family kinase that recognizes the AvrPto effector. HopZ3 acts as a virulence factor on tomato by suppressing AvrPto1Psy-triggered immunity. HopZ3 acetylates AvrPto1Psy and the host proteins PTO, SlRIPK and SlRIN4s. Biochemical reconstruction and site-directed mutagenesis experiments suggest that acetylation acts in multiple ways to suppress immune signaling in tomato. First, acetylation disrupts the critical AvrPto1Psy-PTO interaction needed to initiate the immune response. Unmodified residues at the binding interface of both proteins and at other residues needed for binding are acetylated. Second, acetylation occurs at residues important for AvrPto1Psy function but not for binding to PTO. Finally, acetylation reduces specific phosphorylations needed for promoting the immune-inducing activity of HopZ3’s targets such as AvrPto1Psy and PTO. In some cases, acetylation competes with phosphorylation. HopZ3-mediated acetylation suppresses the kinase activity of SlRIPK and the phosphorylation of its SlRIN4 substrate previously implicated in PTO-signaling. Thus, HopZ3 disrupts the functions of multiple immune components and the effectors that trigger them, leading to increased susceptibility to infection. Finally, mass spectrometry used to map specific acetylated residues confirmed HopZ3’s unusual capacity to modify histidine in addition to serine, threonine and lysine residues. 相似文献
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Dahn A Saunders S Hammond JA Carter D Kirjavainen P Anukam K Reid G 《Microbes and infection / Institut Pasteur》2008,10(6):620-627
The aim of the study was to investigate gene expression profiles of post-menopausal women receiving Premarin estrogen replacement therapy (ERT), compared to controls, and to examine any correlations between the bacterial vaginosis (BV) status of the subjects. Based upon an expected finding of a 50-60% difference between gene expression of host antimicrobials with alpha=0.05 (2-sided), beta=0.20 the calculation of 7 subjects per group, led to a sample size of 10 subjects receiving Premarin estrogen replacement therapy and 10 healthy, age-matched controls. Vaginal samples were collected at a single timepoint and processed for RNA recovery and Affymetrix array analysis, as well as Nugent scoring and denaturing gradient gel electrophoresis to identify bacteria. Lactobacillus iners was the most commonly detected species in the normal flora and this was confirmed with L. iners-specific PCR method. Vaginal swabs from 6 Premarin and 8 control vaginal samples provided a non-invasive means to analyze human gene expression. There was no significant up-regulation of cancer-associated gene expression in subject receiving Premarin ERT, but some evidence that the potentially protective innate immunity was reduced in patients with BV. Of those with a normal flora, there was a 2-fold down-regulation of carcinoma associated forkhead box A1 gene expression. BV was associated with 7-fold down-regulation of host antimicrobial colony stimulating factor, -9.83-fold for IL-1alpha, -8.33 for IL-1beta and -3.63 for IL-6. This is the first study to use gene arrays to correlate changes in host expression response to estrogen replacement therapy and BV. 相似文献
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Scott E. Wolkenberg Zhijian Zhao David D. Wisnoski William H. Leister Julie O’Brien Wei Lemaire David L. Williams Marlene A. Jacobson Cyrille Sur Gene G. Kinney Doug J. Pettibone Philip R. Tiller Sheri Smith Christopher Gibson Bennett K. Ma Stacey L. Polsky-Fisher Craig W. Lindsley George D. Hartman 《Bioorganic & medicinal chemistry letters》2009,19(5):1492-1495
Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic properties, including oral bioavailability, is discussed. 相似文献
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Matthew W. VanBrocklin James P. Robinson Todd Whitwam Adam R. Guilbeault Julie Koeman Pamela J. Swiatek George F. Vande Woude Joseph D. Khoury Sheri L. Holmen 《Pigment cell & melanoma research》2009,22(4):454-460
While many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen‐activated protein kinase signaling pathway. In this study, we used a Cdkn2a‐deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a‐deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency. 相似文献
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Zhao Z O'Brien JA Lemaire W Williams DL Jacobson MA Sur C Pettibone DJ Tiller PR Smith S Hartman GD Wolkenberg SE Lindsley CW 《Bioorganic & medicinal chemistry letters》2006,16(23):5968-5972
This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors. 相似文献