Method for Increasing the Susceptibility of Peptide Deformylase Inhibitors by Using Efflux Pump Inhibitors
OwnerCharles Richard Dean, Neil Stewart Ryderinventors
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Abstract
The present invention provides methods and compositions for increasing the susceptibility of PDF inhibitors against Gram-negative organisms by using efflux pump inhibitors.
Claims24
A method for treating a Gram-negative bacterial infection in a mammal comprising administering an effective amount of a compound of formula (I)
- wherein
- X is —CH2—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—, wherein R is alkyl;
- R1 is aryl or heteroaryl;
- each of R2, R3, R4 and R5, independently, is hydrogen or alkyl, or
- R2 or R3 and R4 or R5, collectively, form a C4-7cycloalkyl;
- and
- n is 0-3, provided that when n is 0, X is —CH2—,
- or a salt thereof or a prodrug thereof;
- and an efflux pump inhibitor.
The method of claim 11, wherein the compound of formula (III) is
A method for treating a Gram-negative bacterial infection in a mammal which is caused by Gram-negative bacteria possessing an RND efflux pump, the method comprising administering an effective amount of the compound
- and an efflux inhibitor that inhibits the RND efflux pump in the Gram-negative bacteria.
A method for increasing the susceptibility of Gram-negative bacteria to a compound of formula (I):
- wherein
- X is —CH2—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—, wherein R is alkyl;
- R1 is aryl or heteroaryl;
- each of R2, R3, R4 and R5, independently, is hydrogen or alkyl, or
- R2 or R3 and R4 or R5 collectively form a C4-7cycloalkyl;
- and
- n is 0-3, provided that when n is 0, X is —CH2—;
- or
- a salt thereof or a prodrug thereof, the method comprising:
- contacting the bacteria with the compound of formula (I) and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in the Gram-negative bacteria.
A method for increasing the susceptibility of Gram-negative bacteria possessing an RND efflux pump to the compound
- comprising contacting the Gram-negative bacteria with the compound and an efflux pump inhibitor in an amount effective to inhibit the RND pump in the Gram-negative bacteria.
A pharmaceutical composition comprising a compound of formula (I)
- wherein
- X is —CH2—, —S—, —CH(OH)—, —CH(OR)—, —CH(SH)—, —CH(SR)—, —CF2—, —C═N(OR)— or —CH(F)—, wherein R is alkyl;
- R1 is aryl or heteroaryl;
- each of R2, R3, R4 and R5, independently, is hydrogen or alkyl, or
- R2 or R3 and R4 or R5, collectively, form a C4-7cycloalkyl;
- and
- N is 0-3, provided that when n is 0, x is —CH2—,
- or a salt thereof or a prodrug thereof, an efflux pump inhibitor and a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.