Abstract
Infections by Pseudomonas aeruginosa are difficult to cure due to its high intrinsic and acquired antibiotic resistance. Once colonized the human host, and thanks to antibiotic treatment pressure, P. aeruginosa usually acquires genetic mutations which provide bacteria with antibiotic resistance as well as ability to better adapt to the host environment. Deciphering the evolutionary traits may provide important insights into the development of effective combinatory antibiotic therapy to treat P. aeruginosa infections. In this study, we investigated the molecular mechanisms by which a clinical isolate (ISP50) yields a carbapenem-resistant derivative (IRP41). RNAseq and genomic DNA reference mapping were conducted to compare the transcriptional profiles and in vivo evolutionary trajectories between the two isolates. Our results demonstrated that oprD mutation together with ampC hyper-expression contributed to the increased resistance to carbapenem in the isolate IRP41. Furthermore, a ldcA (PA5198) gene, encoding murein tetrapeptide carboxypeptidase, has been demonstrated for the first time to negatively influence the ampC expression in P. aeruginosa.
Highlights
Pseudomonas aeruginosa, as an opportunistic human pathogen, is one of the leading causes of nosocomial infections worldwide (Vincent et al, 1995)
We examined minimum inhibitory concentration (MIC) of imipenem, meropenem and biapenem, three carbapenem antibiotics, for all the strains in Table 2 and Supplementary Table S3
AmpC expression is regulated by AmpR, a LysR family transcriptional regulator (Kong et al, 2005)
Summary
Pseudomonas aeruginosa, as an opportunistic human pathogen, is one of the leading causes of nosocomial infections worldwide (Vincent et al, 1995). The mechanisms of carbapenem resistance are usually multifactorial which include: (i) acquisition of carbapenemase encoding genes through horizontal gene transfer (Poole, 2011; Potron et al, 2015), (ii) deficiency or repression of the porin (OprD) for carbapenem (Davies et al, 2011; Poole, 2011), (iii) overexpression of mexAB-oprM efflux pump (Poole, 2011; Liu et al, 2013; Choudhury et al, 2015), and (iv) overexpression of the chromosomal gene (ampC) encoding the P. aeruginosa intrinsic cephalosporinase (Poole, 2011; Mirsalehian et al, 2014). These and other studies have described the associated mechanisms of carbapenem resistance among clinical isolates of P. aeruginosa, there is little information on the detailed molecular mechanisms leading to the evolutionary dynamics of clinical P. aeruginosa isolates from carbapenems susceptibility to resistance and the impact of each of these resistance mechanisms
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