Vancomycin Sensitization in Pseudomonas aeruginosa is Contingent on Limited Metabolic Flux

The global antibiotic resistance crisis causes nearly 5 million deaths annually. Pseudomonas aeruginosa, a virulent Gram-negative bacterium, is a major cause of hospital-acquired infections, often coexisting withStaphylococcus aureus. Previous studies showed P. aeruginosa can be sensitized to vancomycin through altered nutrient availability. This study explores the scope and mechanisms of this phenomenon using a dual-pronged approach focused on primary metabolism. Through the application of a tool compound that targets succinate dehydrogenase, we sought to correlate this sensitization to effects seen in minimal media growth. Carbon supplementation can partially restore tolerance with sources that aid in detecting environmental changes, low iron levels, and altered metabolism. Vancomycin sensitization was also observed in multidrug-resistant clinical isolates, indicating that compensatory mutations may influence antibiotic susceptibility and metabolic flux. Our findings show that P. aeruginosa can also be sensitized to other gram-positive-specific antibiotics, such as erythromycin, chloramphenicol, and amoxicillin, with no apparent correlation to the antibiotic’s size or mechanism. These findings highlight how different growth conditions affect the susceptibility of P. aeruginosa to clinically relevant antibiotics.