Antimicrobial/adjuvant compounds and methods
Inventors
Wu, Fan • Lu, Erhu • Barden, Christopher J.
Assignees
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Publication Number
US-9012655-B2
Publication Date
2015-04-21
Expiration Date
Abstract
Among other things, in general, antimicrobial and/or adjuvant compounds are provided according to Formula Ia: (Ia) in which E and R1-11 have the meanings described herein; and prodrugs and pharmaceutically acceptable salts thereof. Other formulae and methods of use are also provided.
Core Innovation
The invention provides antimicrobial compounds and antimicrobial-adjuvant compounds defined by a sulfur-containing ring within Formula I and Formula Ia, and related formulations. The compounds include prodrugs and pharmaceutically acceptable salts, and they incorporate a variable linker E that is either —CH2— or absent, such that the sulfur-containing ring is directly connected to phenyl when E is absent.
The scaffold further specifies substituent selections for R1-R11 and ring-forming connections, including possibilities where R1 and R2 form a phenyl or benzofuran ring and where R9 and R10 form a phenyl or benzofuran ring. The compound design is tied to inhibition of acyl carrier protein (ACP) synthase (AcpS).
The patent states a therapeutic concept in which microbial infections are treated by administering the antimicrobial compound alone or in combination with an antimicrobial adjuvant. The scope includes embodiments focused on Gram-positive bacteria and enumerates target pathogens and diseases.
Claims Coverage
The consolidated content includes one independent compound claim with broad structural coverage and one independent use/treatment claim framework. Across these, the claims emphasize a sulfur-containing-ring scaffold with variable connectivity (E as —CH2— or absent) and multiple constrained substituent selections, with follow-on coverage for administering an effective amount to a patient and for infections substantially caused by Gram-positive bacteria.
Sulfur-containing ring compound with variable e connectivity and defined substituents
A compound having a sulfur-containing ring, or prodrugs or pharmaceutically acceptable salts thereof, of Formulas I in which E is —CH2— or is absent whereby the sulfur-containing ring is directly connected to phenyl, with defined selections for R1, R2, R9, R10, R11 (if present), and with additional constraints for R3, R8, R4, R7, and R5 and R6.
Treating microbial infection by administering an effective amount
A method for treating a microbial infection by administering an effective amount of the antimicrobial compound to a patient who needs it.
Microbial infection substantially caused by gram-positive bacteria
The method of treatment is for a microbial infection that is substantially caused by Gram-positive bacteria.
Overall claim coverage centers on sulfur-containing-ring antimicrobial compounds defined by Formulas I with constrained substituent options, and on therapeutic methods involving administration of an effective amount to treat microbial infections, including infections substantially caused by Gram-positive bacteria.
Stated Advantages
Provides in vitro AcpS inhibition activity (% activity at 500 nM) for the described compounds.
Provides antimicrobial activity as measured by MIC determinations against MRSA and E. coli D22.
Provides broader MIC panel activity across multiple Gram-positive pathogens.
Reports antibiotic adjuvant activity of selected compounds with erythromycin or ampicillin in Ps. aeruginosa.
Broad disruption of microbial viability.
Potential adjuvant effects when antimicrobial potency is low.
Documented Applications
In vitro AcpS inhibition evaluation using an AcpS inhibition assay (% AcpS activity) with apo-carrier protein (ACP) and [3H]acetyl-CoA.
Antimicrobial evaluation via MIC determinations, including MRSA and E. coli D22 and broader Gram-positive pathogen panels, with additional Gram-positive species including Enterococcus faecalis, Enterococcus faecium, Staphylococcus epidermidis, Bacillus cereus, and Streptococcus pneumoniae Group A.
Assessment of antibiotic adjuvant activity with erythromycin or ampicillin in Ps. aeruginosa.
Treating microbial infections by administering the antimicrobial compound alone or in combination with an antimicrobial adjuvant.
Treating microbial infections substantially caused by Gram-positive bacteria.
Treating infections involving pathogens including methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Acinetobacter baumanii, Stenotrophomonas maltophilia (S. maltophilia), Mycobacterium tuberculosis, and vancomycin-resistant Enterococcus (VRE).
Treatment area listings include skin and skin structure infections; ulcers/wounds/diabetic foot/osteomyelitis/pneumonia/impetigo/anthrax.
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