Metabolically stable N-acylaminooxadiazoles useful as antibacterial agents
Inventors
Aron, Zachary D. • Kwasny, Steven M. • Torhan, Matthew C. • Barbor, Jay P. • Cardinale, Steven C. • Butler, Michelle M. • Opperman, Timothy J. • Keiler, Kenneth C.
Assignees
Penn State Research Foundation • Microbiotix Inc
Publication Number
US-11505533-B2
Publication Date
2022-11-22
Expiration Date
2038-08-21
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Abstract
The present invention is related to the development of therapeutics and prophylactics for the treatment and/or prevention of bacterial infections in humans and other mammals. A new class of small molecules is disclosed that inhibits the bacterial trans-translation/ribosome rescue mechanism and thus blocks infection of host cells by bacteria. Also disclosed are methods of using the small molecule inhibitors in the treatment/prevention of bacterial infections.
Core Innovation
The present invention identifies, isolates, and characterizes small molecule inhibitors of bacterial trans-translation, particularly metabolically stable N-acylaminooxadiazole derivatives containing ureido or aromatic amido moieties. These compounds act as novel broad-spectrum inhibitors of the trans-translation/ribosome rescue mechanism, a pathway essential for bacterial viability or virulence in many species. The inhibitors are suitable for the treatment and/or prevention of bacterial infections in mammals, especially humans.
The invention addresses the immediate need for new antibiotics to combat multidrug-resistant bacteria, such as multidrug-resistant Neisseria gonorrhoeae, extensively drug-resistant and multidrug-resistant Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus, among others. The increased prevalence of multidrug resistance has severely limited treatment options, leaving patients vulnerable to dangerous infections and necessitating the development of drugs with new mechanisms of action.
The compounds described herein function by inhibiting trans-translation, a ribosome rescue mechanism crucial for most bacteria but absent in metazoans. The invention provides methods for synthesizing these compounds, their use in pharmaceutical compositions, and methods of treating and preventing bacterial infections by administering at least one of the inhibitors. The patent also describes the use of these compounds in disinfection and protection of surfaces from bacterial contamination or colonization.
Claims Coverage
The claims center on a class of N-acylaminooxadiazole compounds, their pharmaceutical compositions, methods of using them to treat or prevent bacterial infections, methods of inhibiting bacterial growth or disinfecting surfaces, and specific structural embodiments.
Compound of Formula I as a trans-translation inhibitor
A compound having the structure of Formula I, wherein: - R1, R2, R3, and R4 each independently represent defined aryl, heteroaryl, cycloalkyl, heterocyclic or aliphatic groups; and - the compound may be a pharmaceutically acceptable salt thereof. This feature explicitly covers the specified chemical space of N-acylaminooxadiazole derivatives with ureido or aromatic amido moieties capable of inhibiting bacterial trans-translation.
Method of treating or preventing bacterial infection in mammals using Formula I compounds
A method comprising administering to a subject in need thereof at least one compound of Formula I for the treatment or prevention of bacterial infection in a mammal, including humans. The method may be used for infections caused by M. tuberculosis, N. gonorrhoeae, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis, and S. pneumoniae.
Method of inhibiting trans-translation-mediated bacterial growth in mammals
A method comprising administering an effective amount of at least one compound of Formula I to inhibit trans-translation-mediated bacterial growth in a mammal, including humans.
Pharmaceutical composition comprising Formula I compounds
A pharmaceutical composition comprising at least one compound of Formula I and a pharmaceutically acceptable carrier or excipient.
Method of inhibiting growth or disinfecting bacterial cells on solid surfaces
A method comprising contacting a solid surface with at least one compound of Formula I to inhibit bacterial growth or disinfect the surface. This includes applying to medical devices or equipment such as implantable medical devices, catheters, pumps, heart valves, pacemakers, respirators, and others specified in the claims.
Compound of Formula Ia and uses thereof
A compound having the structure of Formula Ia, as defined in the claims, and pharmaceutically acceptable salts thereof. Further includes methods of treating or preventing bacterial infections in mammals, inhibiting trans-translation-mediated bacterial growth, pharmaceutical compositions, inhibiting growth/disinfecting solid surfaces, and applications to specified devices, as described for Formula I.
The claims comprehensively protect ureido and amido N-acylaminooxadiazole compounds, their methods of use in treating or preventing bacterial infections, their use in inhibiting bacterial growth or disinfecting surfaces, and pharmaceutical compositions containing these compounds.
Stated Advantages
The compounds have potent and broad protection against bacterial infections, including multidrug-resistant pathogens.
Inhibitors based on these compounds are metabolically stable and suitable for administration to mammals, including humans.
They act via a novel mechanism (trans-translation inhibition), sidestepping existing resistance mechanisms in bacteria.
These compounds exhibit low to sub-micromolar inhibitory potency and are generally stable to microsomal degradation, enhancing their drug-like properties.
There is minimal likelihood of target-related toxicity in mammals since trans-translation genes are not found in metazoans.
Pharmaceutical compositions may be formulated for multiple administration routes, including oral, parenteral, and topical, allowing for convenient dosing.
Documented Applications
Treatment and prevention of bacterial infections in mammals, particularly infections caused by multidrug-resistant or extensively drug-resistant bacteria such as Neisseria gonorrhoeae, Mycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus, S. flexneri, H. influenzae, S. aureus, S. enterica, Y. pestis, F. tularensis, and S. pneumoniae.
Use as adjuncts to existing antibiotic therapies or in combination with other antibiotics, such as colistin, for improved activity and spectrum.
Disinfection and inhibition of bacterial growth on solid surfaces, including bandages, bodily appliances, catheters, surgical instruments, implantable medical devices, central venous catheters, implantable pumps, heart valves, pacemakers, heart-lung machines, dialysis equipment, artificial respirators, breathing apparatuses, water pipes, plumbing fixtures, air ducts, and filters.
Sterilization or pretreatment of surfaces colonized by bacteria to kill or prevent bacterial growth.
Use in pharmaceutical compositions for oral, parenteral (including intravenous, intramuscular, subcutaneous, intraperitoneal), or topical administration in mammals.
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