Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria

Area of Science:

• Microbiology
• Pharmacology
• Biochemistry

Background:

• Multi-drug-resistant (MDR) bacteria pose a significant threat to public health, necessitating novel therapeutic strategies.
• Antibiotic adjuvant therapy, combining existing antibiotics with non-antimicrobial small molecules, offers a promising alternative to developing new antibiotics.
• Colistin, a last-resort antibiotic, is crucial for treating MDR Gram-negative bacterial infections, but resistance mechanisms are a growing concern.

Purpose of the Study:

• To investigate the potential of eukaryotic phosphatase inhibitors as adjuvants to overcome colistin resistance.
• To identify specific phosphatase inhibitors that can either break colistin resistance or potentiate its activity.

Main Methods:

• A high-content screen of eukaryotic kinase inhibitors was previously conducted.
• This study explored repurposing eukaryotic phosphatase inhibitors as colistin adjuvants from a panel of 48 compounds.
• Evaluated the synergistic effects of identified compounds with colistin against MDR bacteria.

Main Results:

• The natural product kuwanon G was identified as an effective adjuvant that breaks colistin resistance.
• The non-antimicrobial macrolide ascomycin was found to potentiate colistin activity in polymyxin-susceptible bacteria.
• These findings highlight the therapeutic potential of specific phosphatase inhibitors in combination with colistin.

Conclusions:

• Eukaryotic phosphatase inhibitors represent a viable class of compounds for repurposing as antibiotic adjuvants.
• Kuwanon G and ascomycin demonstrate distinct mechanisms in enhancing colistin's efficacy against challenging bacterial infections.
• This research contributes to the development of strategies to combat antimicrobial resistance and preserve the utility of last-resort antibiotics.