Modulators of methylation for control of bacterial virulence

Details Modulators of methylation for control of bacterial virulence Modulators of methylation for control of bacterial virulence

2002-12-30

2003-10-14

Meller, Michael (Department: 1654)

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Transferases

C435S183000, C435S232000

Reexamination Certificate

active

06632430

ABSTRACT:

TECHNICAL FIELD
The invention relates to the control of bacterial infection in animals. More particularly, it relates to the use of inhibitors of bacterial transmethylation pathways to control such infection.
BACKGROUND ART
The importance of transmethylation reactions in metabolism in general has gained considerable recognition. PCT application WO96/20010 and U.S. Pat. No. 5,872,104, incorporated herein by reference, describe the use of methylation inhibitors to reduce the resistance of microorganisms to antibiotics. Heithoff, D. M., et al,.
Science
(1999) 284:967-970 report the results of a study showing that
Salmonella typhimurium
which lacks DNA adenine methylase (Dam) were essentially avirulent and therefore could be used as live vaccines against murine typhoid fever. The authors concluded that Dam regulated the expression of at least 20 genes known to be induced during infection and noted that inhibitors of Dam were likely to be antimicrobials. It was earlier shown by Braaten, B. A., et al,.
Cell
(1994) 76:577-588 that the methylation patterns associated with pyelonephritis-associated pili (Pap) DNA controlled gene expression in
E. coli
. Thus, it is clear that in bacteria, methylation status is significant in controlling metabolism, and thus infectivity in general. The importance of S-adenosyl-L-methionine (SAM) dependent transmethylation in viral infection has also been studied by Liu, S., et al.,
Antiviral Research
(1992) 19:247-265.
S-adenosyl-homocysteine hydrolase (SAHH) is significantly related to transmethylation by virtue of its ability to regulate the ratio of SAM to S-adenosylhomocysteine (SAH). SAHH catalyzes the equilibrium between SAH and its lysis products, adenosine and homocysteine. It is significant in regulating the levels of adenosine as well. SAHH has been used as a target for antiparasitic and antiviral chemotherapy as described by Minatto, et al,.
Experimental Parasitol
(1998) 175-180. SAM is the source of methyl groups for all transmethylation reactions and SAH constitutes a methylation inhibitor. Thus, if SAHH which controls the ratio of SAM to SAH is inhibited, this will result in modulating the transmethylation metabolism of the bacterium, and consequently, the virulence of the bacterium. Methylation processes are also affected by methionine levels, and agents that deplete methionine, such as methionine-&agr;,&ggr;-lyase (methioninase) are effective to modulate methylation status as well.


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Braaten, B.A. et al. (1994)Cell76:577-588.
Heithoff, D.M. et al. (1999)Science284:967-970.
Liu, S. et al. (1992)Antiviral Research19:247-265.
Minatto, et al. (1998)Exp Parasitology: 175-180.

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