Antimicrobial Resistance: Two-Component Regulatory Systems and Multidrug Efflux Pumps

Abstract

The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell contributing to multidrug resistance (MDR) and, consequently, to the failure of anti-infective therapies. The expression of multidrug efflux pumps can be under the control of transcriptional regulators and two-component systems (TCS). TCS are a major mechanism by which microorganisms sense and reply to external and/or intramembrane stimuli by coordinating the expression of genes involved not only in pathogenic pathways but also in antibiotic resistance. In this review, we describe the influence of TCS on multidrug efflux pump expression and activity in some Gram-negative and Gram-positive bacteria. Taking into account the strict correlation between TCS and multidrug efflux pumps, the development of drugs targeting TCS, alone or together with already discovered efflux pump inhibitors, may represent a beneficial strategy to contribute to the fight against growing antibiotic resistance.

Characterization of genes related to the efflux pump and porin in multidrug-resistant Escherichia coli strains isolated from patients with COVID-19 after secondary infection

“…For example, resistance nodulation division transporters play an important role in mediating bacterial resistance to antibiotics and heavy metals. Furthermore, a mutation in specific amino acid residues in strategic domains of these efflux pumps may represent a mechanism to reduce or inhibit the affinity of the efflux pump for their usual substrates, improving multidrug resistance [ 56 ]. Sulavik et al (2001) created E. coli strains with null mutations in efflux pump genes.…”

“…They also discovered that the overlapping substrate susceptibility profiles of the acrAB and tolC mutant strains support their interaction as a tripartite pump system [ 57 ]. E. coli K-12 has also been reported to have at least 20 multidrug efflux pump genes that confer resistance once overexpressed [ 56 ].…”

A review of the mechanisms that confer antibiotic resistance in pathotypes of E. coli

“…YajR, EmrD, and MdfA in E. coli are examples of DHA1 transporters that have been specifically defined by their conformation. These transporters show the main helices that medicines preferentially target ( Yin et al., 2006 ; De Gaetano et al., 2023 ).…”

“…Recently, P. aeruginosa was shown to contain the novel PACE transporter PA2889. Regardless of pH, PA2880 transports chlorhexidine and produces dimers in a solution, similar to AceI ( De Gaetano et al., 2023 ).…”

Outer Membrane Proteins and Efflux Pumps Mediated Multi-Drug Resistance in Salmonella: Rising Threat to Antimicrobial Therapy

“…OmpD membrane protein allows the passive diffusion associated with OmpC and OmpF. At low pH and in anaerobiosis, the expression of OmpD increases, whereas the expressions of OmpC and OmpF are well regulated, even to irregular osmolality in Salmonella . , Structural changes in the OmpF, hydrogen bonding, and van der Waals interactions in the amino acid result in reduced penetration of antibiotics. , The penetration of cipro­floxacin in regular and altered OmpF is elucidated in Figure .…”