Antimicrobial therapy for bacterial infections
View Patent ↗The disclosure provides a molecular genetic approach of targeted mutagenesis and heterologous expression, coupled with in vitro and in vivo models of bacterial pathogenesis, to demonstrate that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.
1. A method of treating a Staphylococcus sp, having decreased susceptibility to a vancomycin, or for treating a vancomycin-resistant Staphylococcus sp, bacterial infection, comprising:
(1) providing a pharmaceutical composition comprising a small molecule selected from 2-diethylaminoethyl-2,2-diphenyl-valerate; 2,4-dichloro-6-phenylphenoxyethylamine; 2,4-dichloro-6-phenylphenoxyethyldiethylamine; a piperonyl butoxide; or any combination thereof, that inhibits or slows the production and/or activity of a carotenoid in a bacteria; and
(2) administering to a subject inflicted with the Staphylococcus sp, bacterial infection a therapeutically effective dose of the pharmaceutical composition,
wherein a therapeutically effective dose inhibits or slows the production and/or activity of a carotenoid in the bacteria, thereby causing the bacteria to be more susceptible to oxidative damage and/or killing by neutrophils, and the therapeutically effective dose is a dose that is not directly cytotoxic to the bacteria.
2. The method of claim 1 , wherein the carotenoid is a Staphylococcus sp, carotenoid.
3. The method of claim 1 , wherein the bacteria is a Staphylococcus aureus , or the carotenoid is a Staphylococcus aureus carotenoid.
4. The method of claim 1 , wherein the small molecule is a mixed function oxidase inhibitor.
5. The method of claim 4 , wherein the mixed function oxidase inhibitor comprises a 2-diethylaminoethyl-2,2-diphenyl-valerate; a 2,4-dichloro-6-phenylphenoxyethylamine; a 2,4-dichloro-6-phenylphenoxyethyldiethylamine; a piperonyl butoxide; or any combination thereof.
6. The method of claim 1 , wherein the pharmaceutical composition is applied on or with a catheter.
7. The method of claim 1 , wherein the small molecule carotenogenesis inhibitor inhibits the activity of or the expression of: a beta-carotene hydroxylase, a p-carotene desaturase; a dehydrosqualene synthase; a dehydrosqualene desaturase; or a combination thereof.
8. A method of treating a Staphylococcus sp, bacterial infection, or enhancing the efficacy of a vancomycin treatment for a Staphylococcus sp, bacterial infection, to a subject in need thereof, comprising:
(a) providing:
(i) a pharmaceutical composition comprising a small molecule selected from 2-diethylaminoethyl-2,2-diphenyl-valerate; 2,4-dichloro-6-phenylphenoxyethylamine; 2,4-dichloro-6-phenylphenoxyethyldiethylamine; a piperonyl butoxide; or any combination thereof, that inhibits or slows the production and/or activity of a carotenoid in a bacteria, and
(ii) a vancomycin;
(2) administering to the subject inflicted with the Staphylococcus sp, bacterial infection a therapeutically effective dose of the pharmaceutical composition and the vancomycin,
wherein a therapeutically effective dose inhibits or slows the production and/or activity of a carotenoid in the bacteria, and the therapeutically effective dose is a dose that is not directly cytotoxic to the bacteria, thereby causing the Staphylococcus sp, to be more susceptible to oxidative damage and/or killing by neutrophils and enhancing the efficacy of the vancomycin treatment for a Staphylococcus sp, bacterial infection.
9. The method of claim 8 , wherein the carotenoid is a Staphylococcus sp, carotenoid.
10. The method of claim 8 , wherein the bacteria is a Staphylococcus aureus , or the carotenoid is a Staphylococcus aureus carotenoid.
11. The method of claim 8 , wherein the small molecule is a mixed function oxidase inhibitor.
12. The method of claim 11 , wherein the mixed function oxidase inhibitor comprises a 2-diethylaminoethyl-2,2-diphenyl-valerate; a 2,4-dichloro-6-phenylphenoxyethylamine; a 2,4-dichloro-6-phenylphenoxyethyldiethylamine; a piperonyl butoxide; or any combination thereof.
13. The method of claim 11 , wherein the pharmaceutical composition is applied on or with a catheter.
14. The method of claim 11 , wherein the small molecule carotenogenesis inhibitor inhibits the activity of or the expression of: a beta-carotene hydroxylase, a p-carotene desaturase; a dehydrosqualene synthase; a dehydrosqualene desaturase; or a combination thereof.