Drug and Alcohol Rehabilitation: Development of Chlamydial Type III Secretion System Inhibitors for Suppression of Acute and Chronic Forms of Chlamydial Infection?

Development of Chlamydial Type III Secretion System Inhibitors for Suppression of Acute and Chronic Forms of Chlamydial Infection?

Filed under: Drug and Alcohol Rehabilitation

Acta Naturae. 2012 4; 4(2): 87-97
Zigangirova NA, Zayakin ES, Kapotina LN, Kost EA, Didenko LV, Davydova DY, Rumyanceva JP, Gintsburg AL

The Type III secretion system (T3SS) is currently considered to be one of the main pathogenicity factors in Gram-negative bacteria, which exhibit different types of parasitizing activity. The presence of this structure is essential for the development of an acute infection; the chronicity of the infection is fundamentally dependent upon its functioning. In this regard, T3TS is one of the most promising targets for the development of broad-spectrum antimicrobial drugs that do not develop resistance and are efficacious for the acute and chronic forms of infection. The mechanism of action in drug development is based on the specific inhibition of T3SS, which should interrupt the infectious process, thereby enabling the immune system to eliminate the pathogen. As a result of pilot screening using specific cellular and bacterial tests, followed by chemical optimization and detailed characterization of the biological activity, a new class of chlamydial T3SS inhibitors was obtained. The selected compounds have obvious advantages over the currently available inhibitors of T3SS pathogens thanks to the high inhibitory activity of these compounds with minimal damaging effects on eukaryotic cells. Preclinical trials of the selected inhibitors are currently under way.
HubMed – drug


An Analytical Method for Assessing Stage-Specific Drug Activity in Plasmodium vivax Malaria: Implications for Ex Vivo Drug Susceptibility Testing.

Filed under: Drug and Alcohol Rehabilitation

PLoS Negl Trop Dis. 2012 Aug; 6(8): e1772
Kerlin DH, Boyce K, Marfurt J, Simpson JA, Kenangalem E, Cheng Q, Price RN, Gatton ML

The emergence of highly chloroquine (CQ) resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT), originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50)) values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50) for CQ. Our findings indicate that EC(50) values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.
HubMed – drug


Time-Course Proteome Analysis Reveals the Dynamic Response of Cryptococcus gattii Cells to Fluconazole.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(8): e42835
Chong HS, Campbell L, Padula MP, Hill C, Harry E, Li SS, Wilkins MR, Herbert B, Carter D

Cryptococcus gattii is an encapsulated fungus capable of causing fatal disease in immunocompetent humans and animals. As current antifungal therapies are few and limited in efficacy, and resistance is an emerging issue, the development of new treatment strategies is urgently required. The current study undertook a time-course analysis of the proteome of C. gattii during treatment with fluconazole (FLC), which is used widely in prophylactic and maintenance therapies. The aims were to analyze the overall cellular response to FLC, and to find fungal proteins involved in this response that might be useful targets in therapies that augment the antifungal activity of FLC. During FLC treatment, an increase in stress response, ATP synthesis and mitochondrial respiratory chain proteins, and a decrease in most ribosomal proteins was observed, suggesting that ATP-dependent efflux pumps had been initiated for survival and that the maintenance of ribosome synthesis was differentially expressed. Two proteins involved in fungal specific pathways were responsive to FLC. An integrative network analysis revealed co-ordinated processes involved in drug response, and highlighted hubs in the network representing essential proteins that are required for cell viability. This work demonstrates the dynamic cellular response of a typical susceptible isolate of C. gattii to FLC, and identified a number of proteins and pathways that could be targeted to augment the activity of FLC.
HubMed – drug


A comparison of computational methods for identifying virulence factors.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(8): e42517
Zheng LL, Li YX, Ding J, Guo XK, Feng KY, Wang YJ, Hu LL, Cai YD, Hao P, Chou KC

Bacterial pathogens continue to threaten public health worldwide today. Identification of bacterial virulence factors can help to find novel drug/vaccine targets against pathogenicity. It can also help to reveal the mechanisms of the related diseases at the molecular level. With the explosive growth in protein sequences generated in the postgenomic age, it is highly desired to develop computational methods for rapidly and effectively identifying virulence factors according to their sequence information alone. In this study, based on the protein-protein interaction networks from the STRING database, a novel network-based method was proposed for identifying the virulence factors in the proteomes of UPEC 536, UPEC CFT073, P. aeruginosa PAO1, L. pneumophila Philadelphia 1, C. jejuni NCTC 11168 and M. tuberculosis H37Rv. Evaluated on the same benchmark datasets derived from the aforementioned species, the identification accuracies achieved by the network-based method were around 0.9, significantly higher than those by the sequence-based methods such as BLAST, feature selection and VirulentPred. Further analysis showed that the functional associations such as the gene neighborhood and co-occurrence were the primary associations between these virulence factors in the STRING database. The high success rates indicate that the network-based method is quite promising. The novel approach holds high potential for identifying virulence factors in many other various organisms as well because it can be easily extended to identify the virulence factors in many other bacterial species, as long as the relevant significant statistical data are available for them.
HubMed – drug


Coalition tackles heroin abuse issue

Filed under: Drug and Alcohol Rehabilitation

WAUSAU — Heroin abuse has grown to epidemic proportions and central Wisconsin leaders are trying to raise awareness about the deadly drug and prevention and treatment options. About 75 people, including representatives from local police, medical …
Read more on Marshfield News-Herald


The Addictions Coach Utilizes New Technology to Combat Drug and Alcohol

Filed under: Drug and Alcohol Rehabilitation

Cali Estes, The Addictions Coach, utilizes the world of Skype and FaceTime to reach more clients than a traditional rehab or therapy setting. She is paving the way to industry change with new technology. miami, FL, August 11, 2012 –(PR.com)– The …
Read more on PR.com (press release)


Marijuana Debate Rages in Chile

Filed under: Drug and Alcohol Rehabilitation

… 1” in Chile's drug laws alongside cocaine and heroin—4.2 percent of Chileans smoke marijuana, according to a 2010 survey conducted by SENDA, Chile's National Service for the Prevention and Rehabilitation of the Consumption of Drugs and Alcohol.
Read more on Americas Quarterly (blog)


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