Tuesday, July 15, 2014

In Search of New Classes of Antibiotics

Over the history of medicine, the development of antibiotics (1930 – 1980) to combat virulent and dangerous infections has saved countless lives and helped avoid the onset of dangerous pandemics.  The use of these antibiotics has been of immense value in increasing the longevity of human populations.

Antibiotics currently fit into five classes as described in the following table –

Mode of Action
Inhibits bacterial cell wall biosynthesis
Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus
Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome
Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome
Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA

Note: Antibiotics are of no use in treating viral infections since the biology of the virus is markedly different than that of bacterial agents.

However, no new classes of antibiotics have been developed since 1980 and the overuse of the standard antibiotics has led to the insidious development of antibiotic –resistant strains of disease like tuberculosis (TB) and gonorrhea.  From a public health perspective, it is of enormous importance to encourage the development of new classes of antibiotics with unique modes of action.

Wednesday, July 2, 2014

Nature of the Resistance of Flavivirus Infection to Host Cell Defenses

Flaviviruses (FVs) represent a family of viral pathogens responsible for human life-threatening diseases such as Dengue Fever, West Nile, Yellow Fever and Japanese Encephalitis.   The infectious agent within this family of viruses is single-stranded RNA.  During the process of infection (through arthropod vectors), the viral genome (gRNA) is successfully replicated and  subgenomic flaviviral  RNAs (sfRNAs) are also produced.  In animal studies, it has been demonstrated that these sfRNAs are an integral part of the disease process.  It is interesting to note that these sfRNAs are produced as a result of the incomplete degradation of gRNA by the host-derived exonuclease Xm1 – an enzyme that is a part of the host cell defense against infection.  In this scenario, host cell defenses inadvertently play a crucial role in producing disease.

This resistance to complete degradation of gRNA by Xm1 has been shown to be due to specific RNA sequences that are referred to as Xm1-resistant RNAs (xrRNAs).  It is therefore of interest to more fully understand the molecular structure of xrRNAs and, therefore, elucidate the nature of the resistance to the action of Xm1.

Dr. Erich G. Chapman and his colleagues at the Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado at Denver focused their research efforts on establishing the unique and precise structural aspects of xrRNAs  that make them impervious  to Xm1-mediated degradation.

As a result of their extensive analysis they were able to show that the three-dimensional structure of xrRNAs consist of a “ringlike” conformation that prevents Xm1 from breaking down sfRNAs.  In addition, the investigators purposefully disrupted this structure and effectively prevented the formation of sfRNAs during infection.  This is an important finding; for, it helps clarify the mechanism of FV infections that impact many individuals throughout the world.