Protein adhesins as vaccine antigens for Group A Streptococcus.

Group A Streptococcus (GAS) is a globally important human pathogen that causes a broad spectrum of disease ranging from mild superficial infections to severe invasive diseases with high morbidity and mortality. Currently, there is no vaccine available for human use. GAS produces a vast array of virulence factors including multiple adhesin molecules. These mediate binding of the bacteria to host tissues and are essential in the initial phases of infection. Prophylactic vaccination with adhesins is a promising vaccine strategy and many GAS adhesins are currently in development as vaccine candidates. The most advanced candidates, having entered clinical trials, are based on the M protein, while components of the pilus and a number of fibronectin-binding proteins are in pre-clinical development. Adhesin-based vaccines aim to induce protective immunity via two main mechanisms: neutralisation where adhesin-specific antibodies block the ability of the adhesin to bind to host tissue and opsonisation in which adhesin-specific antibodies tag the GAS bacteria for phagocytosis. This review summarises our current knowledge of GAS adhesins and their structural features in the context of vaccine development.

Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin.

Infection by one of the 4 distinct serotypes of dengue virus (DENV) threatens >40% of the world's population, with no efficacious vaccine or antiviral agent currently available. DENV replication through the virus-encoded nonstructural protein (NS) 5 protein occurs in the infected cell cytoplasm, but NS5 from DENV2 has thus far been shown to localize strongly in the nucleus throughout infection. Here we use specific antibodies cross-reactive with NS5 from DENV1-4 to demonstrate nuclear localization of NS5 from all DENV serotypes for the first time in both infected as well as transfected cells, although to differing extents. The small-molecule inhibitor Ivermectin was inhibitory towards both DENV 1 and 2 NS5 interaction with its nuclear transporter importin α/ß in vitro, and protected against infection from DENV1-4. Ivermectin thus has potential in the clinical setting as a dengue antiviral.

Modulation of drug resistance mediated by loss of mismatch repair by the DNA polymerase inhibitor aphidicolin.

Loss of expression of mismatch repair (MMR) proteins leads to resistance of tumor cells to a variety of DNA-damaging agents, including bifunctional alkylating and monofunctional methylating agents such as cis-diaminedichloroplatinum II (CDDP) and N'-methyl-N-nitrosourea (MNU). It has been suggested that coupling to cell death does not occur in the absence of MMR, but instead, DNA lesions are bypassed during replication, giving a drug-tolerant phenotype. In the present study, we have used aphidicolin (Ap), an inhibitor of DNA polymerases, to study the role of replicative bypass in drug resistance mediated by loss of MMR. We have examined the survival of matched ovarian carcinoma cell lines with known MMR status after sequential treatment with CDDP or MNU and Ap. We show that Ap increases the sensitivity of MMR-deficient cell lines to CDDP and MNU to a greater extent than their MMR-proficient counterparts. Furthermore, loss of MMR correlates with loss of CDDP-induced G2 arrest, but this is partially restored after Ap treatment. These data support Ap sensitizing drug-resistant cancer cells that have lost MMR to CDDP and MNU and suggest that the potential use of Ap as a modulator of drug resistance should be targeted to MMR-defective tumors.

Resistance to gentamicin: a growing concern.

Gentaminic was introduced in 1969 as a broad-spectrum aminoglycoside effective in vitro against a majority of aerobic gram-negative bacilli. In recent years gentamicin-resistant clinical isolates have become more prevalent. In our laboratory in 1975, 32% of Pseudomonas sp and 44% of indole-negative Proteus sp isolates were resistant to gentamicin. Resistance to tobramycin is also increasing; 24% of Escherichia coli and 28% of indole-negative Proteus sp isolates were found to be tobramycin-resistant. In addition, isolation of previously uncommon gentamicin-resistant species, ie, Proteus rettgeri and other indole-positive Proteus sp, from clinical specimens has increased dramatically in the past five years. This increase in gentamicin and tobramycin-resistant gram-negative bacilli serves as a constant stimulus for the development of new antimicrobial agents.