Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-14
2002-12-31
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S356000, C546S001000, C546S329000, C546S318000, C546S339000, C546S347000, C548S469000, C548S509000, C548S518000, C424S404000
Reexamination Certificate
active
06500852
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to antibacterial and antimicrobial agents. In particular, the present invention provides methods of synthesizing and screening compounds that are bacterial nicotinamide adenine dinucleotide (NAD) synthetase enzyme inhibitors. The present invention also provides novel compounds that inhibit bacterial NAD synthetase enzyme. The invention also provides libraries of compounds that comprise bacterial NAD synthetase enzyme inhibitors. Further, the present invention provides compounds that exhibit therapeutic activity as antibacterial agents, antimicrobial agents and broad spectrum antibiotics. Still further, the invention provides methods of treating a mammal with bacterial NAD synthetase enzyme inhibitor compounds. The present invention also provides novel disinfecting agents.
BACKGROUND OF THE INVENTION
Drug-resistant infectious bacteria, that is, bacteria that are not killed or inhibited by existing antibacterial and antimicrobial compounds, have become an alarmingly serious worldwide health problem. (E. Ed. Rubenstein,
Science
, 264, 360 (1994)). In fact, a number of bacterial infections may soon be untreatable unless alternative drug treatments are identified.
Antimicrobial or antibacterial resistance has been recognized since the introduction of penicillin nearly 50 years ago. At that time, penicillin-resistant infections caused by
Staphylococcus aureus
rapidly appeared. Today, hospitals worldwide are facing unprecedented crises from the rapid emergence and dissemination of microbes resistant to one or more antimicrobial and antibacterial agents commonly in use today. As stated in the Fact Sheet on Antimicrobial Resistance of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, several strains of antibiotic-resistant bacteria are now emerging and are becoming a threat to human and animal populations, including those summarized below:
1) Strains of
Staphylococcus aureus
resistant to methicillin and other antibiotics are endemic in hospitals. Infection with methicillin-resistant
S. aureus
(MRSA) strains may also be increasing in non-hospital settings. Vancomycin is the only effective treatment for MRSA infections. A particularly troubling observation is that
S. aureos
strains with reduced susceptibility to vancomycin have emerged recently in Japan and the United States. The emergence of vancomycin-resistant strains would present a serious problem for physicians and patients.
2) Increasing reliance on vancomycin has led to the emergence of vancomycin-resistant enterococci (VRE), bacteria that infect wounds, the unnary tract and other sites. Until 1989, such resistance had not been reported in U.S. hospitals. By 1993, however, more than 10 percent of hospital-acquired enterococci infections reported to the Centers for Disease Control (“CDC”) were resistant.
3)
Streptococcus pneumoniae
causes thousands of cases of meningitis and pneumonia, as well as 7 million cases of ear infection in the United States each year. Currently, about 30 percent of
S. pneumoniae
isolates are resistant to penicillin, the primary drug used to treat this infection. Many penicillin-resistant strains are also resistant to other antimicrobial or antibacterial drugs.
4) Strains of multi-drug resistant tuberculosis (MDR-TB) have emerged over the last decade and pose a particular threat to people infected with HIV. Drug-resistant strains are as contagious as those that are susceptible to drugs. MDR-TB is more difficult and vastly more expensive to treat, and patients may remain infectious longer due to inadequate treatment. Multi-drug resistant strains of
Mycobacterium tuberculosis
have also emerged in several countries, including the U.S.
5) Diarrheal diseases cause almost 3 million deaths a year, mostly in developing countries, where resistant strains of highly pathogenic bacteria such as
Shigella dysenteriae
, Campylobacter,
Vibrio cholerae, Escherichia coli
and Salmonella are emerging. Furthermore, recent outbreaks of Salmonella food poisoning have occurred in the United States. A potentially dangerous “superbug” known as
Salmonella typhimurium
, resistant to ampicillin, sulfa, streptomycin, tetracycline and chloramphenicol, has caused illness in Europe, Canada and the United States.
In addition to its adverse effect on public health, antimicrobial or antibacterial resistance contributes to higher health care costs. Treating resistant infections often requires the use of more expensive or more toxic drugs and can result in longer hospital stays for infected patients. The Institute of Medicine, a part of the National Academy of Sciences, has estimated that the annual cost of treating antibiotic resistant infections in the United States may be as high as $30 billion.
Given the above, it would be highly desirable to develop novel antibacterial and antimicrobial agents that act by different mechanisms than those agents in use currently. Further, it would be desirable to be able to synthesize such novel compounds. It would also be desirable to develop libraries of compounds that exhibit inhibitory bacterial NAD synthetase activity. Such new agents would be useful to counteract antibiotic resistant strains of bacteria and other types of harmful microbes. It would be even more desirable to develop antibacterial agents that inhibit or block essential bacterial metabolic mechanisms, to result in bacterial death or deactivation, without also affecting the essential metabolic activities of a mammalian host. That is, it would be desirable to develop antibacterial agents that preferentially attack bacteria and other microbes and kill or deactivate the harmful organism without causing any attendant undesirable side effects in a human or animal patient. It would also be desirable to develop methods of rapidly screening potential new antimicrobial and antibacterial agents. It would also be desirable to develop novel disinfecting agents.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a NAD synthetase inhibitor compound of the formula:
Still further, the invention provides a bacterial NAD synthetase enzyme inhibitor compound of the structure:
In yet a further embodiment, the invention provides a bacterial NAD synthetase enzyme inhibitor formula:
In a further aspect, the invention provides a bacterial NAD synthetase enzyme inhibitor compound, having Structure 2:
wherein n is an integer of from 1 to 12, R
1
-R
7
. each, independently, is an H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group, wherein the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group and wherein the linker may also contain heteroatoms.
In yet another aspect, the invention provides a bacterial NAD synthetase enzyme inhibitor compound, having Structure 4:
wherein X is a C, N, O or S within a monocyclic or bicycle moiety, A and B represent the respective sites of attachment or the linker, n is an integer of from 1 to 12, R1-R7 each, independently, is an H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, wherein the linker is a saturated or unsaturated cyclic group or an aliphatic branched or unbranched alkyl, alkenyl or alkynyl group, and wherein the linker may also contain heteroatoms.
Further, the invention provides a method of treating or preventing a microbial infection in a mammal comprising administering to the mammal a treatment effective or treatment preventive amount of a bacterial NAD synthetase enzyme inhibitor compound. Still further, a method is provided of killing a prokaryote with an amount of prokaryotic NAD synthetase enzyme inhibitor to reduce of eliminate the production of NAD whereby the prokaryote is killed. Moreover, a method is provided of decreasing prokaryotic growth, comprising contacting the prokaryote with an amount of a prokaryotic NAD synthetase enzyme inhibitor effective to reduce or eliminate the production of NAD whereby prokaryotic growth is decrea
Brouillette Christie G.
Brouillette Wayne J.
Cristofoli Walter
DeLucas Lawrence J.
Devedjiev Yancho
Patel Sudhaker B.
Shah Mukund J.
University of Alabama Research Foundation
Womble Carlyle Sandridge & Rice PLLC
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