US 2017/0246149 A1 · COMPOSITIONS AND METHODS FOR TREATING MICROBIAL INFECTIONS

Abstract

Embodiments of the presently-disclosed subject matter include activators of HssRS that induce endogenous heme biosynthesis by perturbing central metabolism. These molecules are toxic to fermenting S. aureus, including clinically relevant small colony variants (SCVs). The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. This small molecule is a powerful tool not only for studying bacterial heme biosynthesis and central metabolism, but also establishes targeting of fermentation as a viable antibacterial strategy.

Claims20

Dependent claims

A method for treating a microbial infection, comprising:

administering an effective amount of a fermentation inhibitor, comprising a compound of the formula:
wherein,
R1 is H, alkyl, aryl, or heteroaryl;
R2 is H, halogen, alkyl, aryl, or heteroaryl;
R3 is H, halogen, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, or acetamide;
R4 is H, halogen, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, or acetamide;
R5 is H, halogen, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, or acetamide;
R6 is H, halogen, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, or acetamide;
and
R7 is H, halogen, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, or acetamide;
wherein R5 and R6, R7 and R6, R5 and R4, R4 and R3 can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R3.

8 more elements

A composition, comprising:

a fermentation inhibitor comprising a compound of the formula
and salts thereof
wherein,
R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl;
R3 is H, hydroxyl, alkoxy, amino, amino sulfonyl, acetamide;
R4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
wherein R5 and R4, can cyclize forming a 3-10 member ring comprising C, O, S, and/or N optionally substituted with one or more R3;
and wherein when R1, R2, R4, R5, R6, and R7 are H, R3 is H;
and wherein when R2 is heteroaryl or aryl and R3 is hydroxyl, R1 is H, aryl, alkyl, heteroaryl;
R4 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R5 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R6 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
R7 is H, hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
and wherein when R3, R4 R5 R6 are H, R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl;
and R7 is hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
and wherein when R4, R5, R6 and R7 are H, R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl, and R3 is hydroxyl, alkoxy, amino, amino sulfonyl, acetamide;
and wherein when R3, R5 R6 and R7 are H, R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl, and R4 is hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
and wherein when R3, R4, R6 and R7 are H, R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl, R5 is hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide;
and wherein when R3, R4, R5 and R7 are H, R1 is H, aryl, alkyl, heteroaryl;
R2 is H, alkyl, aryl, heteroaryl, and R6 is hydroxyl, alkoxy, alkyl, aryl, heteroaryl, amino, amino sulfonyl, acetamide.

25 more elements

Dependencies are inferred from the claim text.

Compositions and methods for treating microbial infections

Life of this patent

Compositions and methods for treating microbial infections

Life of this patent

Abstract

Claims20