Small molecule inhibitors of bacterial efflux pumps and methods of using same
An empirical Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae (SAFIRE) was developed. Using this methodology, a library of small molecules and identified antimicrobials that are cell permeable and non-host-toxic were screened. Inhibitors of bacterial efflux pumps were identified as being implicated in antibiotic resistance and are attractive therapeutic targets for antimicrobials.
1. A pharmaceutical composition comprising an effective amount of an efflux pump modulator compound and a pharmaceutically acceptable carrier, wherein the efflux pump modulatory compound has one of the structure:
(EPM30)
(EPM35), or
(EPM43).
2. A method of treating a bacterial pathogen in a subject, the method comprising administering to the subject a therapeutically effective amount of an efflux pump modulator (EPM) compound, wherein the EPM is
3. The method of claim 2 , further comprising administering an antimicrobial peptide or an antibiotic.
4. The method of claim 3 , wherein the antibiotic comprises tetracycline.
5. The method of claim 3 , wherein the antimicrobial peptide comprises polymyxin B.
6. The method of claim 2 , wherein the EPM compound comprises EPM30.
7. The method of claim 2 , wherein the EPM compound comprises EPM35.
8. The method of claim 2 , wherein the EPM compound comprises EPM43.
9. The method of claim 2 , wherein the bacterial pathogen comprises one or more of a Salmonella sp., K. pneumoniae, Enterobacter cloacae , or E. coli.
10. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable carrier is present an amount ranging from 1-99%.
11. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is an aqueous composition which is formulated at a pharmaceutically acceptable pH and tonicity.