ABSTRACT
The first targeted inhibitors of an essential M. tuberculosis cell wall lipase, Rv3802c, are described. Lead compounds exhibited nanomolar inhibition of the enzyme, and encouraging antibacterial activity against M. tuberculosis in vitro, supporting Rv3802c as a novel TB drug target.
Subject(s)
Anti-Bacterial Agents/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/antagonists & inhibitors , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Cell Wall/drug effects , Lipase/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Mycobacterium/drug effects , Tuberculosis/microbiology , Drug Design , Humans , Mycobacterium tuberculosis/enzymologySubject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Hydro-Lyases/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Catalysis , Models, Molecular , Mycobacterium tuberculosis/enzymologyABSTRACT
Discovery and characterization of novel secreted enzymes of Mycobacterium tuberculosis are important for understanding the pathogenesis of one of the most important human bacterial pathogens. The proteome of M. tuberculosis contains over 400 potentially secreted proteins, the majority of which are uncharacterized. A family of seven cutinase-like proteins (CULPs) was identified by bioinformatic analysis, expressed and purified from Escherichia coli, and characterized in terms of their enzymatic activities. These studies revealed a functional diversity of enzyme classes based on differential preferences for substrate chain length. One member, Culp1, exhibited strong esterase activity, 40-fold higher than that of Culp6, which had strong activity as a lipase. Another, Culp4, performed moderately as an esterase and weakly as a lipase. Culp6 lipase activity was optimal above pH 7.0, and fully maintained to pH 8.5. None of the CULP members exhibited cutinase activity. Site-directed mutagenesis of each residue of the putative catalytic triad in Culp6 confirmed that each was essential for activity toward all fatty acid chain lengths of nitrophenyl esters and lipolytic function. Culp1 and Culp2 were present only in culture supernatants of M. tuberculosis, while Culp6, which is putatively essential for mycobacterial growth, was retained in the cell wall, suggesting the proteins play distinct roles in mycobacterial biology.
Subject(s)
Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Carboxylic Ester Hydrolases/chemistry , Carboxylic Ester Hydrolases/metabolism , Catalytic Domain , Mycobacterium tuberculosis/enzymology , Amino Acid Sequence , Animals , Bacterial Proteins/classification , Bacterial Proteins/genetics , Carboxylic Ester Hydrolases/classification , Carboxylic Ester Hydrolases/genetics , Cholinesterase Inhibitors/metabolism , Humans , Molecular Sequence Data , Mutagenesis, Site-Directed , Mycobacterium tuberculosis/genetics , Paraoxon/metabolism , Phylogeny , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino AcidABSTRACT
In this existential-phenomenological investigation, women whose partners were mandated to attend a batterers' intervention program (BIP) were interviewed about their experiences before their partner attended his first class. The goal of this study was to gain an understanding of the woman's expectations of the BIP in the aftermath of her experience of abuse and her reasons for maintaining the relationship. Women described their experience as one of living in a dangerous environment that keeps them nervous, confused, fearful, and feeling bad about themselves, but yet hopeful that the abuse will stop now that their partner is being sent to treatment. BIP was, in fact, the "last hope," an optimism unsupported by current research data.
Subject(s)
Battered Women/psychology , Crime Victims , Domestic Violence , Interpersonal Relations , Program Development , Adaptation, Psychological , Adult , Affect , Attitude , Fear , Female , HumansABSTRACT
TOPIC: Intimate partner violence continues to be a confounding national health problem, especially for women and children. Certified batterers' intervention programs are one means currently being used to combat intimate partner violence. METHOD: Existential phenomenology was utilized in this qualitative study to gain an understanding of the perceptions of the perpetrator prior to beginning a batterer intervention program. FINDINGS: The batterer's experience is divided into two major themes: lack of justification of behaviors toward him and minimization and justification of his behaviors toward the victim and others. CONCLUSIONS: It is hoped that obtaining this understanding will encourage program personnel working in the area of batterers' intervention programs to include more emotional skills training within such programs, thus improving the quality of life for victims, perpetrators, and their families.
Subject(s)
Battered Women , Cognitive Behavioral Therapy/methods , Deception , Domestic Violence/legislation & jurisprudence , Mandatory Programs/statistics & numerical data , Adult , Female , Humans , MaleABSTRACT
Anonymous data provided by 417 female and 179 male sexually active heterosexual respondents showed that in long term sexual relationships, sexual satisfaction was positively correlated with two different intimacy variables, the respondent's orgasm likelihood, and negatively correlated with conflict in the relationship. Multiple linear regression permitted us to measure the effect sizes of these variables as predictors of sexual satisfaction. These findings have important implications for treatment of symptomatic couples.
