The University of Central Florida invention is an antimicrobial agent that weakens the defenses of gram-negative bacteria, increasing their sensitivity to antibiotics. The intensive, widespread use of antibiotics to treat bacterial infections has led to an increasing number of antibiotic-resistant bacteria. Examples are gram-negative multidrug-resistant (MDR) bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Bacterial membranes form an effective barrier to many antibiotics. In addition, the bacteria’s drug efflux pumps—transport proteins—enable the bacteria to remove toxins (antibiotics) by extruding them out of the bacterial cell.
As a solution, the UCF invention can be used to permeabilize cell membranes and to disrupt the electrical potential inside the bacteria. The action de-energizes the efflux pump and enables antibiotics to remain in the bacteria therefore, increasing the susceptibility of the bacteria to the drug.
Technical Details
The UCF invention consists of compositions and methods for using the antimicrobial action and antibiotic-enhancing properties of motuporamine derivatives (lipophilic polyamines) against gram-negative bacteria. Researchers selected motuporamines (originally isolated from the marine sponge Xestospongia exigua) for their amphiphilic architectures that comprise a large hydrophobic macrocycle with an appended polyamine motif. The motuporamine derivatives were able to disrupt the proton gradient, effectively de-energizing the efflux pump. Also, the researchers found that combining one or more polyamine compounds with antibiotics enables the reduction in doses of both the polyamine compound and antibiotic to ameliorate potential adverse side effects. In one example, motuporamine derivatives, 6a (MOTU-CH2-33) and 6b (MOTU-CH2-44) exhibited excellent antimicrobial activities against many species, including the multidrug-resistant E. aerogenes EA289.
The team also investigated whether derived polyamine agents could restore the potency of the antibiotic doxycycline at well below its minimum inhibitory concentration (MIC). For example, they found that the MIC of doxycycline against P. aeruginosa PAO1 was 16 µg/mL. Yet, using the invention’s polyamine derivatives with doxycycline at a significantly lower concentration (2 µg/mL) restored doxycycline activity against E. aerogenes EA289, P. aeruginosa PAO1, and K pneumoniae KPC2-ST258.
Partnering Opportunity
The research team is seeking partners for licensing and/or research collaboration.
Stage of Development
Motuporamine derivatives tested against various bacterial strains in vitro.
Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram-Negative Bacteria, ChemBioChem. 2017 Feb 1;18(3):276-283.
Antibiotic Adjuvants: Make Antibiotics Great Again!, Journal of Medicinal Chemistry 2019 62 (19), 8665-8681 DOI: https://doi.org/10.1021/acs.jmedchem.8b01781
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