Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-29
2002-07-23
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S311000, C514S312000, C514S314000
Reexamination Certificate
active
06423741
ABSTRACT:
FIELD
The invention is related to the development of strategic and novel anti-microbial composition comprising a arteether, quinolones and similar drugs, which can be used as an advanced generation drug composition against infections and simultaneously to counter the resistance development in bacteria by an in built mechanism of action to eliminate resistant cells.
BACKGROUND OF INVENTION
Since the discovery of penicillin by Alexander Flemming, the developments in drug discovery have undergone a sea of change. With increased and indiscriminate use of drugs, the infectious agents are tending to become resistant by adopting different means for inactivating the drug molecules which otherwise control them by inhibiting their vital life processes. Out of many inhibitory molecules, only a few are used as drugs because many of them are not safe for human and animal consumption. The pace of drug discovery is thus slower than the evolution of newer resistant strains of infectious agents. This is due to the fact that mutations occur spontaneously in a random manner but due to selection pressure by continued presence/administration of antibiotics, the resistant organisms proliferate unlimitedly circumventing the effect of the drug molecules. To counter this drug resistance menace, the existing drugs proven safe for human consumption with minimal side effects are usually modified chemically for more effectiveness. This has led to the development of first generation, second generation and third generation drugs/antibiotics to counter the parallel evolution of resistance. In addition to modifying the structure, another novel but simple way which has been conceived and developed in the present invention is to administer the drugs in combination i. e. the first generation drugs may be used with other safe compound such that the sensitive bacteria can be killed by the first generation antibiotic and the resistance developed if any can be killed by the second compound and conversely the resistant cells against second compound are killed by first antibiotic due to genetic basis of resistance-sensitivity relationship.
In this invention, the applicants used a unique composition of known compounds with different and specific counter modes of actions to control the resistance menace in bacteria. This invention is novel in terms of the idea of combining two known molecules for not only controlling/killing bacteria but also preventing the appearance of resistant strains due to counter-actions wherein, one molecule kills bacteria resistant to other and vice versa and finally leading to prevention of resistance development itself. This phenomenon of sensitivity of cells to the one upon resistance development against other and vice versa is genetically governed, and hence is a self sustaining process once the right kind of anti-microbial molecules have been identified through study of specific mutations, which was achieved in the invention.
The compounds a and &agr; and &bgr; arteethers were synthesized from dihydroartemisinin by etherification with ethanol. These earlier were developed as anti-malarial drugs in India by Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow and Central Drug Research Institute (CDRI), Lucknow, India after phase III clinical trial. Absolute stereochemistry of arteethers at C-12 were also determined and found that it is 2-3 times more potent than artemisinin. In U.S. patent application Ser. No. 09/176,204, the Applicants had demonstrated that the compound a arteether can specifically kill certain drug resistant bacteria, hence capable of being used as an antibiotic.
For bacterial growth, DNA gyrase enzyme is essential for being involved in the replication of DNA and hence cell division. This enzyme transiently breaks the DNA strands and introduces negative superhelical turns in an ATP-dependent process. The
E.coli
DNA gyrase enzyme is a tetramer with two subunits A and B. The subunit A is nalidixic acid sensitive but certain mutation(s) in this subunit makes the bacteria resistant to nalidixic acid. In the said U.S. patent application, the Applicant had shown that normal wild type bacteria are not killed by &agr; arteether but the mutants resistant to nalidixic acid and other fluoroquinolones (with modified gyrase) are highly sensitive to a arteether, whereas the bacteria with normal A subunit are killed by nalidixic acid.
It is also important to note that globally
Mycobacterium tubercztlosis
infects about ten million people killing about three million each year making this bacteria the greatest cause of mortality by any single infectious agent worldwide. Quinolones and derived fluoroquinolones are a part of the common chemotherapy against tuberculosis. Quinolones have been shown to inhibit DNA gyrase activity such as relaxation of DNA supercoiling during the DNA replication. Several investigators have shown that point mutations in gyrA gene located in a very small region between 0-400 nucleotides of the gyrA gene are responsible for quinolone resistance acquired by different strains of
E.coli
selected either in-vitro or in-vivo. The resistance mechanisms that have developed due to mutations in gyrA gene in Mycobacteria are related to
E.coli
. The mechanism of quinolone resistance appears fairly similar between
E.coli
, Mycobacteria,
H. influenzae
and in many other bacteria
In the earlier invention, the applicants had found the novel property of the compound &agr; arteether i. e. it is effective against the gyr mutant (Nal
r
) strains of
E.coli
but ineffective against wild type (Nal
s
) strains. So the applicants thought of combining the already out of use quinolone, nalidixic acid with a arteether to generate a composition in preventing resistance development itself Accordingly, the present application is filed as a continuation-in-part of copending U.S. application Ser. No.09/176,204.
It is also important that these compounds and their activity are already known individually (quinolones since 1960 and &agr; arteether since the Applicants US application). But the activity of the combination of these two are not reported till date and Applicants have developed a composition which is cheap, safe, and wherein the already tested antibiotics can be used in tandem with the already tested safe compound &agr; arteether. The results were fully substantiated with the experimentation in this direction. The two molecules in these combinations killing the resistant bacteria against each other will not permit any resistant strains/mutants to proliferate which constitutes the basis of drug resistance development in microbes.
OBJECTS
The main object of the invention is to develop a novel anti-microbial composition comprising a arteether, quinolones and similar drugs.
Another object is to provide a novel anti-microbial composition useful in countering the development of resistance itself
Yet another object is to develop an anti-microbial composition capable of killing bacteria resistant to conventional drugs and prevent proliferation of resistant or mutant strains of bacteria.
SUMMARY OF THE INVENTION
This invention is related to the development of strategic and novel composition comprising a arteether, quinolones and similar drugs which can be used as advanced generation drug(s) to counter the resistance development itself while, having a potential to be used in treating infectious diseases particularly in those cases where drug resistant strains are known to appear very frequently. The uniqueness and most useful feature is that, because the composition is a combination of &agr; arteether and quinolone drugs, the spontaneous mutants arising resistant to Quinolones or its derivatives will be killed by &agr; arteether and at the same time any &agr; arteether resistant strains become highly sensitive to nalidixic acid and hence eliminated by it through the combination approach. The new composition inhibits the resistance development due to mutation in the gyr A gene of bacteria, in which one component is &agr;-arteether and the other may be nalidixic acid or any of
Darokar Mahendra Pandurang
Jain Dharam Chand
Khanuja Suman Preet Singh
Kumar Sushil
Kumar Tiruppadiripuliyur Ranganathan Santha
Council of Scientific and Industrial Research
Ladas & Parry
Weddington Kevin E.
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