Glutamine Potentiates Cefoperazone-Sulbactam Activity against Acinetobacter baumannii by Increasing Drug Uptake and...

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antibiotic resistance in bacteria, particularly Acinetobacter baumannii, poses a significant global health threat.
• Novel therapeutic strategies combining antibiotics with metabolic modulators are needed to overcome resistance.
• Preclinical pharmacodynamic studies are crucial for validating such combination therapies.

Purpose of the Study:

• To evaluate the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against clinical isolates of Acinetobacter baumannii.
• To assess the synergistic, equivalent, or antagonistic interactions between SCF and glutamine.
• To investigate the impact of glutamine on SCF resistance development and bacterial metabolism.

Main Methods:

• Tested the combination of SCF and glutamine against 237 Acinetobacter baumannii clinical isolates (antibiotic-sensitive, multidrug-resistant, carbapenem-resistant).
• Utilized time-kill assays, bacterial load quantification, and murine infection models to validate findings.
• Analyzed effects on bacterial metabolism, reactive oxygen species (ROS) production, drug uptake, and resistance mechanisms.

Main Results:

• The SCF-glutamine combination exhibited synergistic efficacy in 94.51% of isolates.
• Therapeutic effects were stable across varying calcium concentrations and pH gradients.
• Glutamine was shown to slow SCF resistance, prolong the postantibiotic effect, and reduce mutation frequency.

Conclusions:

• The combination of SCF and glutamine demonstrates potent synergistic activity against multidrug-resistant and carbapenem-resistant Acinetobacter baumannii.
• Glutamine reprograms bacterial metabolism, enhancing ROS production and drug uptake for increased bacterial eradication.
• This synergistic combination represents a promising therapeutic candidate for combating challenging bacterial infections.