Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
1999-12-02
2004-08-31
Wax, Robert A. (Department: 1653)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C435S007100, C435S007330, C435S007800, C435S883000, C536S023700, C530S350000, C530S820000
Reexamination Certificate
active
06783930
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the field of antibacterial agents and the treatment of infections of animals or other complex organisms by bacteria.
The frequency and spectrum of antibiotic-resistant infections have, in recent years, increased in both the hospital and community. Certain infections have become essentially untreatable and are growing to epidemic proportions in the developing world as well as in institutional settings in the developed world. The staggering spread of antibiotic resistance in pathogenic bacteria has been attributed to microbial genetic characteristics, widespread use of antibiotic drugs, and changes in society that enhance the transmission of drug-resistant organisms. This spread of drug resistant microbes is leading to ever increasing morbidity, mortality and health-care costs.
Ironically, it is the very success of antibiotics, resulting in their widespread use, that has contributed the most to rising numbers of drug resistant bacterial strains. The longer a bacterial strain is exposed to a drug, the more likely it is to acquire resistance. Today, a total of 160 antibiotics, all based on a few basic chemical structures and targeting a small number of metabolic pathways, have found their way to market. Over-prescription of these drugs, as well as the failure of patients to comply with the complete antibiotic regimen, has lead to the rapid emergence of antibiotic resistant strains. Such misuse of prescriptions, careless use of antibiotics in virtually all commercial production of beef and fowl, and changing societal conditions, such as the growth of day-care centers, increased long-term care in hospitals, and increased mobility of the population, has provided an environment where drug-resistant microbes can emerge and spread. Thus, virtually all common infectious bacteria are becoming, or have already become, resistant to one or more groups of antibiotics. Such resistance now reaches all classes of antibiotics currently in use, including: &bgr;-lactams, fluoroquinolones, aminoglycosides, macrolide peptides, chloramphenicol, tetracyclines, rifampicin, folate inhibitors, glycopeptides, and mupirocin.
Over the last 45 years bacteria have adapted genetically to avoid the destruction/alteration of the essential pathways that these chemotherapeutic agents target. Antibiotic resistant bacterial strains are now emerging at a higher rate than the rate at which new antibiotics are being developed. The consequence of this dilemma has been a dramatic increase in the cost of treating infections what would otherwise easily succumb to routine antibiotic therapy. Furthermore, and perhaps most importantly, the emergence of multiple drug resistant pathogenic bacteria has led to a significant increase in morbidity and mortality, particularly in institutional settings.
Most major pharmaceutical companies have on-going drug discovery programs for novel anti-microbials. These are based on screens for small molecule inhibitors (natural products, bacterial culture media, libraries of small molecules, combinatorial chemistry) of crucial metabolic pathways of the micro-organism of interest (e.g., bacteria, fungi, parasites, worms). The screening process is largely for cytotoxic compounds and in most cases is not based on a known mechanism of action of the compounds. Pharmaceutical companies have large programs in this area Classical drug screening programs are being exhausted and many of these pharmaceutical companies are looking towards rational drug design programs.
Several small to mid-size biotechnology companies as well as large pharmaceutical companies have developed systematic high-throughput sequencing programs to decipher the genetic code of specific microorganisms of interest. The goal is to identify, through sequencing, unique biochemical pathways or intermediates that are unique to the microorganism. Knowledge of this may, in turn, form the rationale for a drug discovery program based on the mechanism of action of the identified enzymes/proteins. Genome Therapeutics Corp., The Institute for Genome Research, Human Genome Sciences Inc., and other companies have such sequencing programs in place. However, one of the most critical steps in this approach is the ascertainment that the identified proteins and biochemical pathways are 1) non-redundant and essential for bacterial survival, and 2) constitute suitable and accessible targets for drug discovery.
SUMMARY OF THE INVENTION
While animals such as humans are, on occasion, infected by pathogenic bacteria, bacteria also have natural enemies. A number of host-specific viruses, known as bacteriophages or phages, infect and kill bacteria in the natural environment. Such bacteriophages generally have small compact genomes and bacteria are their exclusive hosts. Many known bacteria are host to a large number of bacteriophages that have been described in the literature. During the 1940's-1960's, phage biology was an area of active research. As a testimony to this, the study of phages which infect and inhibit the enteric bacterium
Escherichia coli
(
E. coli
) contributed much to the early understanding of molecular biology and virology.
This invention utilizes the observation that bacteriophages successfully infect and inhibit or kill host bacteria, targeting a variety of normal host metabolic and physiological traits, some of which are shared by all bacteria, pathogenic and nonpathogenic alike. The term “pathogenic” as used herein denotes a contribution to or implication in disease or a morbid state of an infected organism. The invention thus involves identifying and elucidating the molecular mechanisms by which phages interfere with host bacterial metabolism, an objective being to provide novel targets for drug design. Whether the phage blocks bacterial RNA transcription or translation, or attacks other important metabolic pathways, such as cell wall assembly or membrane integrity, the basic blueprint for a phage's bacteria-inhibiting ability is encoded in its genome and can be unlocked using bioinformatics, functional genomics, and proteorics. By these means, the invention utilizes sequence information from the genomics of bacteriophage to identify novel antimicrobials that can be further used to actively and/or prophylactically treat bacterial infection.
Two important components of the invention thus are: i) the identification of bacteria-inhibiting phage open reading frames (“ORF”s) and corresponding products that can be used to develop antibiotics based on amino acid sequence and secondary structural characteristics of the ORF products, and ii) the use of bacteriophages to map out essential bacterial target genes and homologs, which can in turn lead to the development of suitable anti-microbial agents. These two avenues represent new and general methods for developing novel antimicrobials.
The invention thus concerns the identification of bacteriophage ORFs that supply bacteria-inhibiting functions. In this regard, use of the terms “inhibit”, “inhibition”, “inhibitory”, and “inhibitor” all refer to a function of reducing a biological activity or function. Such reduction in activity or function can, for example, be in connection with a cellular component, e.g., an enzyme, or in connection with a cellular process, e.g., synthesis of a particular protein, or in connection with an overall process of a cell, e.g., cell growth. In reference to bacterial cell growth, for example, an inhibitory effect (i.e., a bacteria-inhibiting effect) may be bacteriocidal (killing of bacterial cells) or bacteriostatic (i.e., stopping or at least slowing bacterial cell growth). The latter slows or prevents cell growth such that fewer cells of the strain are produced relative to uninhibited cells over a given period of time. From a molecular standpoint, such inhibition may equate with a reduction in the level of, or elimination of, the transcription and/or translation of a specific bacterial target(s), or reduction or elimination of activity of a particular target biomolecule.
It is particularly
DuBow Michael
Gros Philippe
Pelletier Jerry
Mitra Rita
Wax Robert A.
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