Extended structure-activity relationship studies of the [1,2,5]oxadiazolo[3,4-b]pyrazine-containing colistin...

Area of Science:

• Microbiology
• Medicinal Chemistry
• Infectious Diseases

Background:

• Antimicrobial resistance (AMR) is a critical global health threat, particularly multidrug-resistant (MDR) Gram-negative bacterial infections.
• Colistin, a last-resort antibiotic, faces increasing resistance, limiting treatment options for severe infections.
• Existing treatments are becoming less effective, necessitating novel therapeutic strategies.

Purpose of the Study:

• To discover and develop novel colistin adjuvants that restore antibiotic efficacy against MDR Gram-negative bacteria.
• To investigate the structure-activity relationships (SAR) of [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP) analogs as colistin potentiators.
• To identify compounds with potent antimicrobial activity and low mammalian toxicity.

Main Methods:

• Screening of [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP) derivatives for colistin-sensitizing activity.
• Extensive structure-activity relationship (SAR) studies on ODP analogs with alkyl- or arylalkylamine substituents.
• Evaluation of compound efficacy against a range of clinically relevant MDR Gram-negative pathogens.
• Assessment of mammalian toxicity for promising adjuvant candidates.

Main Results:

• Discovery of a series of bisanilino ODP compounds that act as effective colistin adjuvants.
• Identification of two novel ODP analogs, compounds 5q and 8g, demonstrating potent colistin-potentiating activity.
• Demonstration of low mammalian toxicity for the identified ODP-based colistin potentiators.
• Broad-spectrum efficacy of the new compounds against various MDR Gram-negative bacteria.

Conclusions:

• Novel [1,2,5]oxadiazolo[3,4-b]pyrazine (ODP) analogs can effectively potentiate colistin against multidrug-resistant Gram-negative bacteria.
• Compounds 5q and 8g represent promising candidates for adjunctive therapy to combat challenging bacterial infections.
• The developed ODP-based compounds offer a potential solution to the growing crisis of antimicrobial resistance with favorable safety profiles.