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Structure-Function Studies on IMD-0354 Identifies Highly Active Colistin Adjuvants
Ansley M Nemeth1, Akash K Basak1, Alexander W Weig1
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Abstract:
Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last-resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK-β inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this study, we explore the structure-activity relationship (SAR) between the IMD-0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae.
Insights
New compounds targeting colistin resistance in multidrug-resistant (MDR) Gram-negative bacteria show enhanced potency. This research explores structure-activity relationships to combat the growing threat of untreatable infections.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Multidrug-resistant (MDR) Gram-negative bacterial infections pose a significant global health challenge.
- Increasing colistin resistance limits treatment options for MDR Gram-negative infections, necessitating novel therapeutic strategies.
- Adjuvants that bypass bacterial resistance mechanisms offer a promising approach to combatting antibiotic resistance.
Purpose of the Study:
- To investigate the structure-activity relationship (SAR) of the IKK-β inhibitor IMD-0354 scaffold for suppressing colistin resistance.
- To identify novel compounds with enhanced activity against colistin-resistant Gram-negative bacteria.
Main Methods:
- Exploration of SAR for IMD-0354 derivatives.
- Testing of identified compounds against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae.
Main Results:
- Several IMD-0354 derivatives demonstrated potent suppression of colistin resistance.
- Identified compounds exhibited superior activity compared to the parent compound against resistant bacterial strains.
Conclusions:
- The IMD-0354 scaffold is a viable starting point for developing novel adjuvants to overcome colistin resistance.
- Further development of these compounds could provide new therapeutic options for MDR Gram-negative infections.
