Motuporamine derivatives as antimicrobial agents and antibiotic enhancers against resistant gram-negative bacteria
Inventors
Phanstiel, IV, Otto • Brunel, Jean-Michel
Assignees
Aix Marseille Universite • Centre National de la Recherche Scientifique CNRS • Institut Jean Paoli and Irene Calmettes • Inserm Transfert SA • University of Central Florida Research Foundation Inc
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Publication Number
US-11820726-B2
Publication Date
2023-11-21
Expiration Date
Abstract
Motuporamine agents having antimicrobial activity and uses thereof.
Core Innovation
The patent describes lipophilic motuporamine/polyamine derivatives that function as antimicrobial agents and antibiotic enhancers against resistant Gram-negative bacteria. The compounds act by disrupting or perturbing membrane permeability and by depolarizing the proton gradient, which inhibits RND-family efflux, including AcrAB-TolC.
The description emphasizes specific motuporamine/polyamine derivatives, including compound 5b (MOTU-N44), as a lead compound. It restores doxycycline activity at sub-MIC antibiotic concentrations, shows synergy with certain antibiotics, and is described to increase outer-membrane permeabilization, cause membrane depolarization, and inhibit glucose-triggered efflux.
The description further characterizes efflux inhibition as including de-energization of efflux-pump function using ATP efflux/release and related assays. It also states that the compounds produce rapid bactericidal effects in time-kill assays against EA289 and are discussed within a therapeutic/composition framework that includes treating infections and reducing antibiotic resistance by contacting microbes and by coadministering with antibiotics in compositions including pharmaceutically acceptable carriers or salts.
Claims Coverage
The provided independent claim covers one pharmaceutical composition combining specified motuporamine/polyamine compounds or salts with an antibiotic, where the combination enhances antibiotic activity. The compounds are defined by explicit formulas and parameter mappings.
Motuporamine/polyamine-antibiotic combination composition that enhances antibiotic activity
A composition comprising an effective amount of one or more specified compounds selected from 4a, 4b, 5a, 5b, 6a, 6b, 9a, 9b, 10, 11a, 11b, 11c, 12a, 16a, 16b, 16c, and 50, or pharmaceutically acceptable salts thereof, and an effective amount of an antibiotic, wherein the combination enhances the activity of the antibiotic.
Defined compound identities by explicit formulas and parameter mappings
The compounds 4a, 4b, 5a, 5b, 6a, 6b, 11a, 11b, 11c, 12a, 16a, 16b, 16c, and 50 are defined by the formulae and parameter mappings given in the claim, including explicit definitions for 9a, 9b, 10, and 16a to 16c.
Pharmaceutically acceptable carrier
The composition further includes a pharmaceutically acceptable carrier in a dependent claim.
Coverage is directed to a composition combining a specified antibiotic with one or more defined motuporamine/polyamine compounds or salts to enhance antibiotic activity, with an additional carrier recited in dependent form.
Stated Advantages
Enhances the activity of the antibiotic when combined with the specified compound(s).
Restores doxycycline activity at sub-MIC antibiotic concentrations.
Shows synergy with certain antibiotics.
Produces rapid bactericidal effects in time-kill assays against EA289.
Documented Applications
Treating infections by contacting microbes with the motuporamine/polyamine derivatives.
Reducing antibiotic resistance by contacting microbes with the compounds.
Coadministering the compounds with antibiotics in compositions including pharmaceutically acceptable carriers or salts.
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