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primary topic: In vitro and in vivo investigations into the potential of quinazoline and quinoline derivatives as NorA efflux pump inhibitors against resistant staphylococcus aureus strains

In vitro and in vivo investigations into the potential of quinazoline and quinoline derivatives as NorA efflux pump inhibitors against resistant staphylococcus aureus strains
type: AcademicArticle
type: Article
abstract: Background:Staphylococcus aureus is a highly lethal Gram-positive bacterium that is responsible for over one million deaths annually. As a member of the ESKAPE pathogens, its methicillin-resistant strains (MRSA) are prevalent worldwide and exhibit significant antimicrobial resistance (AMR). Bacterial efflux pumps play a pivotal role in the development of AMR by facilitating the expulsion of a range of antimicrobial agents. Methods: The S. aureus strain SA-1199B, which overexpresses NorA and carries a GrlA mutation, was utilized to comprehensively profile the mechanism of the compounds PQQ16P and PQK4F. To assess the toxicity and genotoxicity of these compounds, RAW macrophages, HEK 293T, and HepG2 cell lines were utilized. Female BALB/c mice were utilized to assess the in vivo synergism of EPIs with CPX, Results: NorA efflux pump inhibitors (EPIs), PQQ16P and PQK4F, enhanced the efficacy of the antibacterial ciprofloxacin (CPX) against resistant S. aureus strains. The mechanism of EPIs involved the inhibition of NorA efflux pump, without compromising bacterial membrane permeability, ATP levels, or mammalian calcium channels. Moreover, the EPIs significantly augmented the bactericidal and post-antibiotic effects of CPX, elevating its mutation prevention concentration without manifesting substantial toxicity to human cells. Furthermore, the EPIs reduced S. aureus invasiveness in macrophages, indicating a role for NorA in bacterial virulence. Notably, the in vivo synergism of these EPIs with CPX was observed in a mouse infection model. Conclusions: This study provides substantial evidence for the potential of employing EPIs in a combination with CPX to counteract AMR, both in vitro and in vivo.
date: 2025-03
volume: 14
issue: 4
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

MDPI AG
type: Organization

Antibiotics (Basel)
type: Collection

Giada Cernicchi
type: Person
given name: Giada
family name: Cernicchi

Mattia Acito
type: Person
given name: Mattia
family name: Acito

Tommaso Felicetti
type: Person
given name: Tommaso
family name: Felicetti

Nishtha Chandal
type: Person
given name: Nishtha
family name: Chandal

Nidhi Sharma
type: Person
given name: Nidhi
family name: Sharma

Hemraj Nandanwar
type: Person
given name: Hemraj
family name: Nandanwar

Tommaso Rondini
type: Person
given name: Tommaso
family name: Rondini

Stefano Sabatini
type: Person
given name: Stefano
family name: Sabatini

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primary topic: In vitro and in vivo investigations into the potential of quinazoline and quinoline derivatives as NorA efflux pump inhibitors against resistant staphylococcus aureus strains