Antibacterial compounds targeting isoprenoid biosynthesis

Patent metadata

Field	Value
Publication number	US-9951097-B2
Application number	US-201314649153-A
Country	US
Kind code	B2
Filing date	Dec 4, 2013
Priority date	Dec 4, 2012
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. The invention provides small molecules that inhibit cellular drug targets such as UPPS and FPPS by interacting with binding pockets, thereby preventing enzyme function. Compounds described herein are also active against Staphylococcus aureus (MIC90˜0.25 μg/mL), can potently synergize with methicillin (fractional inhibitory concentration index=0.25), and are protective in a mouse infection model. The invention therefore provides numerous compounds for anti-bacterial treatments and for restoring sensitivity to drugs such as methicillin, using combination therapies.

First claim

What is claimed is:

1. A method of killing or inhibiting the growth of methicillin-resistant Staphylococcus aureus (MRSA) comprising contacting the MRSA with an effective lethal or inhibitory amount of a compound of Formula V that binds to site 4 of bacterial undecaprenyl diphosphate synthase (UPPS), and further comprising contacting the MRSA with an effective lethal or inhibitory amount of methicillin, and the compound of Formula V is:

wherein each R S is independently a saccharide moiety;
each R 3 is independently hydrogen, alkyl, alkoxy, hydroxy, amino, nitro, halo, or an optionally substituted phenylamide;
n is independently 1, 2, 3, or 4; and
the molecular weight is at least about 300 and less than about 1,200;

or a salt or solvate thereof, thereby killing or inhibiting the growth of the MRSA.

2. The method of claim 1 wherein the compound of Formula V is:

or a salt or solvate thereof.

Assignees

• Univ Illinois
• Univ California

Inventors

• Zhu Wei
• Lindert Steffen
• Zhang Yonghui
• Sinko William
• Li Kai
• Mccammon James Andrew
• Oldfield Eric

Classifications

• A61K31/7034

  attached to a carbocyclic compound, e.g. phloridzin · CPC title

• C07D233/24

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title