Naringenin Microsphere as a Novel Adjuvant Reverses Colistin Resistance via Various Strategies against Multidrug-Resistant Klebsiella pneumoniae Infection

Abstract

The efficacy of colistin, the last option against multidrug-resistant (MDR) Gram-negative bacteria, is severely threatened by the prevalence of plasmid-or chromosome-mediated colistin resistance genes. Herein, naringenin has dramatically restored colistin sensitivity against colistin-resistant Klebsiella pneumoniae infection without affecting bacterial viability, inducing resistance and causing obvious cell toxicity. Mechanism analysis reveals that naringenin potentiates colistin activity by multiple strategies including inhibition of mobilized colistin resistance gene activity, repression of two-component system regulation, and acceleration of reactive oxygen species-mediated oxidative damage. A lung-targeted delivery system of naringenin microspheres has been designed to facilitate naringenin bioavailability, accompanied by an effective potentiation of colistin for Klebsiella pneumoniae infection. Consequently, a new recognition of naringenin microspheres has been elucidated to restore colistin efficacy against colistin-resistant Gram-negative pathogens, which may be an effective strategy of developing potential candidates for MDR Gramnegative bacteria infection.

Bavachin Rejuvenates Sensitivity of Colistin against Colistin-Resistant Gram-Negative Bacteria

“…A comparative assessment of the potential binding capacity of bavachin and MCR protein was performed using molecular docking. The structure of the MCR-1 protein was obtained from the RCSB protein crystals database (PDB entry: 5GRR) [18]. The structure of bavachin was drawn using ChemDraw 16.0 software.…”

“…For example, α-mangostin, a xanthone derivative from the pericarp of Garcinia mangostana L. peel extract, exhibits rapid bactericidal activity against Gram-positive bacteria and enhances the antibacterial activity of colistin against GNB [16,17]. A natural compound naringenin microsphere as the adjuvant reverses colistin resistance against MDR K. pneumoniae infection by various strategies [18]. Thymol, an essential oil from medicinal plants, potentiates the antibacterial activity of colistin by accelerating the damage and permeability of the bacterial outer membrane [19].…”

Colistin the last resort drug in 21st century antibiotics to combat Multidrug resistance superbugs

“…Additionally, it was discovered during these surveys that these adjuvants could boost the efficacy of Colistin by more than 2048 folds. This suggests that lower colistin in-vivo dosage against Colistin in Gram-negative microorganisms may be possible with adjuvant pairing (Wang et al 2018;Sheng et al 2022). This review article investigates the significance of Colistin as a last-resort antibiotic against multidrugresistant Gram-negative bacteria.…”