Motuporamine derivatives as antimicrobial agents and antibiotic enhancers against resistant gram-negative bacteria
Inventors
Phanstiel, IV, Otto • Brunel, Jean-Michel
Assignees
Inserm Transfert SA • University of Central Florida Research Foundation Inc
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Publication Number
US-10710957-B2
Publication Date
2020-07-14
Expiration Date
Abstract
Motuporamine agents having antimicrobial activity and uses thereof.
Core Innovation
Motuporamine derivatives are proposed as antimicrobial agents and antibiotic enhancers against resistant Gram-negative bacteria. The patent defines amphiphilic structural formulae for motuporamine compounds, with variable macrocycle ring size and options for linkers and substituents, and it includes example compounds such as motuporamine compounds 4a–6b, anthracenyl-polyamine derivatives 7a–d, cholic acid-derived macrocycle compounds 16a–c, compound 5b (MOTU-N44), and compound 50.
The problem addressed is the treatment of microbe infection and the need to counter resistant Gram-negative multidrug-resistant bacteria. The patent reports in vitro antimicrobial performance focused on Gram-negative MIC potency and describes antibiotic restoration when used with antibiotics at sub-MIC antibiotic doses, including compound 5b (MOTU-N44) with doxycycline, chloramphenicol, erythromycin, and cefepime.
Mechanistic assays link the enhancer activity to membrane depolarization/permeabilization, disruption of proton-motive force, and inhibition of efflux-pump activity associated with AcrAB-TolC and related efflux readouts, including efflux of ATP and a 1,2’-diNA efflux measurement. Together, these findings support direct inhibition of Gram-negative bacteria and restoration of antibiotic activity by motuporamine derivatives.
Claims Coverage
The independent claim covers administering motuporamine derivative compounds of a specified structural formula to treat microbe infection, with the option to co-administer an antibiotic. The dependent inventive features refine the optional antibiotic selection and add a lower-dosage constraint when used in combination with the specified compounds.
Treating microbe infection with specified motuporamine structural formula compounds
A method of treating a microbe infection in a subject in need of treatment by administering an effective amount of one or more compounds having a specified formula wherein n=10-13; X=CH2 or N; Y=CH2 or N; a=2-8; b=0-8; and R1 and R2 are defined by the listed substitution classes, including pharmaceutically acceptable salts.
Selecting a first enumerated group of antibiotics for optional co-administration
The method further specifies that the antibiotic used is selected from a group consisting of amoxicillin, doxycycline, erythromycin, chloramphenicol, cephalexin, ciprofloxacin, clindamycin, methicillin, metronidazole, penicillin, rifampicin, azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate, levofloxacin, and vancomycin.
Selecting a second enumerated group of antibiotics for optional co-administration
The method further specifies that the antibiotic used is selected from a group consisting of ampicillin, vancomycin, gentamicin, tetracycline, chloramphenicol, rifampin, norfloxacin, rifaximin, tigecycline, furazolidone, triclosan, cefoperazone, silver sulfadiazine, dapsone, gemifloxacin, sulfadimidine, enoxacin, sulfisoxazole, ceftolozane, prontosil, sulfapyridine, sulfamerazine, grepafloxacin, sulfamethoxypyridazine, sulfalene, acetic acid/hydrocortisone, sulfaphenazole, sulfametoxydiazine, sulfamoxole, sulfabenzamide, sulfametrole, viridicatumtoxin B, sulfametomidine, sulfaperin, and sulfathiourea.
Using a lower antibiotic dosage in combination
The method is wherein the antibiotic is effective at a lower dosage in combination with the one or more compounds than without the one or more compounds.
Across the independent and dependent claims, the core coverage is a treatment method that administers effective amounts of compounds defined by a motuporamine structural formula to treat microbe infection, optionally co-administered with an antibiotic. The dependent claims refine co-administration by enumerating antibiotic choices and by requiring that the antibiotic be effective at a lower dosage when combined with the specified compounds.
Stated Advantages
Antibiotic restoration at sub-MIC antibiotic doses when combined with the motuporamine derivatives.
Membrane depolarization/permeabilization effects and disruption of proton-motive force.
Inhibition of efflux pump activity associated with AcrAB-TolC.
Improved Gram-negative MIC potency against resistant Gram-negative bacteria.
Documented Applications
Treating a microbe infection in a subject in need of treatment by administering motuporamine-derivative compounds, optionally together with an antibiotic.
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