The effect of exogenous glutathione on meropenem susceptibility in Klebsiella pneumoniae-carbapenemases (KPC)-producing bacteria.

Abstract

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and Pseudomonas aeruginosa, associated with systemic and hospital-acquired infections, have spread globally and pose a significant public health concern. Glutathione is a multifunctional thiol-antioxidant compound synthesized in most Gram-negative bacteria and crucial in maintaining intracellular redox homeostasis. Exogenous glutathione exhibits antibiotic properties and has differential effects on conventional antibiotics. Therefore, its effect on specific antibiotics needs to be clarified in bacterial species. In this study, we investigated the antibacterial activity of glutathione and its effect on meropenem susceptibility in KPC-producing bacteria. Two major KPC-encoding genes cloned from two different clinical KPC-producing K. pneumoniae were introduced into E. coli and P. aeruginosa. Then, the KPC-producing K. pneumoniae, E. coli, and P. aeruginosa were used for minimum inhibitory concentration (MIC), population analysis, checkerboard, and time-killing assays. The results showed that glutathione exhibited antibacterial activity at >10 mM in K. pneumoniae, E. coli, and P. aeruginosa. MIC levels of meropenem combined with 10 mM of glutathione were synergistically decreased by 8- to ≥ 256-fold in KPC-producing bacteria. Furthermore, this combination killed 100% of the KPC-producing bacteria at 2 to 4 μg mL^-1 of meropenem. These findings suggest that exogenous glutathione may be applicable in fighting infections caused by KPC-producing bacteria.