Compounds and methods for modulating communication and virulence in quorum sensing bacteria
AssigneeWisconsin Alumni Research Foundation
InventorsHelen E. BLACKWELL, Grant D. Geske, Rachel Wezeman
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Abstract
The present invention provides compositions and methods for modulating the communication and virulence of quorum sensing bacteria. In various exemplary embodiments, the invention provides a combinatorial library of quorum sensing compounds including synthetic analogs of naturally occurring and non-naturally occurring acyl-homoserine lactone (AHL) analogs, and methods of synthesizing and using these compounds.
Claims25
-8. (canceled)
A method of synthesizing acyl-homoserine lactone analogs comprising the steps of:
- loading amino polystyrene resin with an N-9-fluorenylmethoxycarbonyl-L-methionine using microwave-assisted carbodiimide coupling;
- removing the 9-fluorenylmethoxycarbonyl-L-methionine group via thermal assistance using microwave-assisted carbodiimide coupling of carboxylic acids;
- and
- releasing acyl-homoserine lactone analogs from the solid support by reacting L-methionine with cyanogen bromide.
A method of synthesizing autoinducer analogs comprising the steps of:
- providing a halide derivatized substrate;
- (a) acid coupling the halide derivatized substrate;
- (b) forming an epoxide of resulting compound of step (a);
- (c) opening the epoxide ring of the compound in step (b);
- (d) deprotecting the resulting compound of step (c);
- (e) acylating the resulting compound of step (d);
- (f) cyclizing the resulting compound of step (e);
- and
- (g) cleaving the resulting autoinducer analog of step (f) from the substrate.
The method of claim 25, wherein modulating or regulating infectivity and pathogenicity of quorum sensing bacteria comprises reducing the virulence of quorum sensing bacteria.
(canceled)
A compound of formula:
- where n is 1, 2 or 3, R3 is selected from —H, —CH2CH3, or —CH3, R4 is selected from —H, or —CH2—R5, where R5 is —H, and R1 is —CH2COR2 where R2 is
A method for modulating or regulate infectivity and pathogenicity of quorum sensing bacteria which comprises comprising contacting a quorum sensing bacterium with one or more compounds selected from the group consisting of
- (a) a compound of the formula:
- where:
- n is 1, 2 or 3;
- R1 is selected from the group consisting of —H, —(CH2)aCH3, —(CH2)aCOR2, —(CH2)aCHOHR2, —(CH2)aR6, —O—(CH2)aCH3, —(CH2)aHC═CH, —HC═CH(CH2)aCH3, —(CH2)aHC═CH(CH2)bCH3, —HC═CHR7, —C≡CR7, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted phenyl, substituted and unsubstituted naphthly, three to eight member substituted and unsubstituted heterocyclic rings, where the heteroatom is at least one of O, S or N;
- R2 is selected from the group consisting of —H, —(CH2)aCH3, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted phenyl, substituted and unsubstituted naphthyl, and three to eight member substituted and unsubstituted heterocyclic rings, where the heteroatom is at least one of O, S or N,
- R3 is selected from the group consisting of —H, —CH2CH3, and —CH3;
- R4 is selected from —H, or —CH2—R5, where R5 is selected from —I, —N(CH3)2, —N(CH2HC═CH2)2,
- R6 or R7 are the same or different, and are selected from the group consisting of —H, substituted and unsubstituted C3-C8 cycloalkyl, substituted and unsubstituted phenyl, substituted and unsubstituted naphthyl, three to eight member substituted and unsubstituted heterocyclic rings, where the heteroatom is at least one of O, S or N;
- and
- a and b are, independently, 0 or integers from 1 to 15;
- (b) a compound selected from compounds 40-44 having formulas:
- (c) a compound selected from compounds 50, 51, 53-59 having formulas:
- (d) a compound selected from compounds:
- and
- (e) a compound of formula:
- where n is 1, 2 or 3, R3 is selected from —H, —CH2CH3, or —CH3, R4 is selected from —H, or —CH2—R5, where R5 is —H, and R1 is —CH2COR2 where R2 is
Dependencies are inferred from the claim text.