<p>Mechanisms of Heteroresistance and Resistance to Imipenem in <em>Pseudomonas aeruginosa</em></p>

Abstract

Background: Heteroresistance is a phenomenon that occurs in all bacteria and can cause treatment failure. Yet, the exact mechanisms responsible for heteroresistance still remain unknown. The following study investigated the mechanisms of imipenem-heteroresistance and -resistance in Pseudomonas aeruginosa clinical isolates from Wenzhou, China. Methods: Imipenem resistance was detected by the agar dilution method; heteroresistance was determined by population analysis profiles. Biofilm formation assay and modified carbapenem inactivation methods were also performed. Polymerase chain reaction (PCR) was conducted to detect oprD, and quantitative real-time PCR was used to determine expression levels of oprD, ampC and four efflux pump coding genes (mexB, mexD, mexE and mexY). Results: Six imipenem-heteroresistant and -resistant P. aeruginosa isolates were selected respectively. Deficient oprD was detected in all resistant isolates and two heteroresistant isolates. No strains produced carbapenemases. Expression levels of oprD were downregulated in heteroresistant isolates. Transcription levels of the mexE and mexY were significantly increased in all heterogeneous subpopulations compared with their respective native ones. Compared with the susceptible group, increased mean relative expression levels of mexE and mexY or the decreased mean relative expression levels of oprD were observed in the resistant group (P < 0.05), whereas transcription levels of the mexB and mexD remained unchanged. Conclusion: Down-regulation of oprD contributed to the resistance and heteroresistance of imipenem in our P. aeruginosa clinical isolates. In addition, the marginal up-regulation of efflux systems may indirectly affect imipenem resistance. Contrarily, defective oprD was less common in our experimental heteroresistant strains than resistant strains.

Genomic Characterization of Imipenem- and Imipenem-Relebactam-Resistant Clinical Isolates of Pseudomonas aeruginosa

“…However, due to the amino acid variability within the susceptible group, we could not determine any significant mutation that might correlate with their resistance to Im; thus, other molecular mechanisms may take place. Our results agree with previous reports that indicated that truncated OprD proteins are responsible for the resistance to Im ( 29 ).…”

It’s Not Easy Being Green: A Narrative Review on the Microbiology, Virulence and Therapeutic Prospects of Multidrug-Resistant Pseudomonas aeruginosa

“…Since then, a variety of novel MBLs have been described in Gram-negative bacteria, including AIM (Australian Imipenemase), DIM (Dutch Imipenemase), GIM (German Imipenemase), KHM (Kyorin University Hospital), NDM (New Delhi MBL), SIM (Seul Imipenemase), SPM (Sao Paulo MBL), and TMB (Tripoli MBL) [219,220]. In laboratory conditions, carbapenemases may be differentiated through the inhibition of various molecules (e.g., ethylenediaminetetraacetic acid for MBLs, boronic acid for serine-type enzymes), but it is more difficult to carry out due to the low outer membrane permeability of P. aeruginosa, which may significantly alter the resistance phenotype [221,222].…”

Antibiotic Heteroresistance in Klebsiella pneumoniae

“…For example, heteroresistance to tigecycline in Salmonella enterica was associated with an increased level of the RamA transcriptional factor, resulting in the overexpression of the AcrAB-TolC and OqxAB efflux pumps [ 35 ]. Other studies have indicated that the downregulation of the OprD porin and overexpression of the efflux systems contributed to carbapenem and imipenem heteroresistance in Pseudomonas aeruginosa [ 38 , 41 ].…”