16-methyl-oxacyclohexadecan-2-one and 16-methyl-azacyclohexadecan-2-one derivatives as antimicrobial agents
Inventors
Stierle, Andrea • Stierle, Donald • PRIESTLEY, Nigel
Assignees
University of Montana Missoula
Publication Number
US-11401253-B2
Publication Date
2022-08-02
Expiration Date
2038-03-20
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Abstract
16-membered macrolide compounds inhibit growth of various microbial species and have utility in the treatment of systemic or topical microbial infections, including methicillin-resistant strains (Formula I).
Core Innovation
The invention concerns novel 16-membered macrolide compounds and their pharmaceutically acceptable salts, as well as associated pharmaceutical compositions and methods of use. These compounds, described by formula (I), lack the sugar moieties that are generally considered essential for the activity of conventional macrolide antibiotics. Distinctively, these compounds, including derivatives such as BPL 76, BPL 81, and their analogs, do not block bacterial protein synthesis by interacting with the bacterial ribosome.
The core problem addressed is the increasing resistance of microbial species, including both bacteria and fungi, to known antibiotics, particularly macrolides. Existing macrolide antibiotics have led to drug-resistant strains of Staphylococcus, Enterococcus, and other pathogens. There is a critical, unmet need for new drugs with broad-spectrum activity, especially those effective against drug-resistant microbes.
The described macrolide compounds demonstrate effective inhibition of various microbial species—including gram-positive and certain gram-negative bacteria, as well as fungi—without conforming to the structural or mechanistic paradigms of existing macrolide antibiotics. The invention extends to pharmaceutical compositions containing these compounds and to methods for treating systemic or topical microbial infections or inhibiting microbial growth, including infections by methicillin-resistant strains.
Claims Coverage
There are four principal inventive features outlined across four independent claims covering new compounds, pharmaceutical compositions, and methods of use.
16-membered macrolide compounds of formula (I) and salts
The invention includes compounds of formula (I), or pharmaceutically acceptable salts thereof, as defined in detail with specific groups for X1, R1, R2, R3, L1, L2, and further substituents and stereochemistry, including selected derivatives named explicitly. These novel macrolides notably lack sugar moieties typical of traditional macrolide antibiotics, and include both oxygen- and nitrogen-containing macrocycles.
Pharmaceutical composition comprising the novel compound
The inventive feature includes a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, combined with a pharmaceutically acceptable carrier. The scope covers any such composition with the defined macrolide compounds.
Method of treating microbial infection with the compound
A method of treating a microbial infection is claimed, comprising administering a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject infected with a microbe.
Method for inhibiting microbial growth with the compound
The inventive feature covers contacting a microbe with a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to inhibit microbial growth.
In summary, the claims provide coverage for new, structurally distinct 16-membered macrolides, compositions containing them, and their use in treating or inhibiting microbial infections.
Stated Advantages
Compounds show activity against multi-drug resistant bacteria as well as antibiotic-susceptible bacteria.
The compounds have a unique mechanism of action among macrolides and do not block bacterial protein synthesis, reducing the risk of inducing bacterial antibiotic resistance typical of conventional macrolides.
The lead compounds have low or greatly diminished toxicity toward mammalian cells, providing a wide therapeutic index.
Documented Applications
Use in the treatment or prevention of systemic or topical microbial infections in a subject, including infections by methicillin-resistant bacterial strains.
Inhibition of microbial growth by contacting a microbe with the compound, applicable for anti-microbial uses in vitro or ex vivo.
Treatment of yeast infections by administering a therapeutically effective amount of the compound.
Use as an antimicrobial agent in cell culture, or for decontamination, antiseptic, sterilization purposes, including application to surfaces, products, devices, or systems susceptible to microbial growth.
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