Abstract
The opportunistic human pathogen Pseudomonas aeruginosa is responsible for ~ 10% of hospital-acquired infections worldwide. It is notorious for its high level resistance toward many antibiotics, and the number of multi-drug resistant clinical isolates is steadily increasing. A better understanding of the molecular mechanisms underlying drug resistance is crucial for the development of novel antimicrobials and alternative strategies such as enhanced sensitization of bacteria to antibiotics in use. In P. aeruginosa several uptake channels for amino-acids and carbon sources can serve simultaneously as entry ports for antibiotics. The respective genes are often controlled by carbon catabolite repression (CCR). We have recently shown that Hfq in concert with Crc acts as a translational repressor during CCR. This function is counteracted by the regulatory RNA CrcZ, which functions as a decoy to abrogate Hfq-mediated translational repression of catabolic genes. Here, we report an increased susceptibility of P. aeruginosa hfq deletion strains to different classes of antibiotics. Transcriptome analyses indicated that Hfq impacts on different mechanisms known to be involved in antibiotic susceptibility, viz import and efflux, energy metabolism, cell wall and LPS composition as well as on the c-di-GMP levels. Furthermore, we show that sequestration of Hfq by CrcZ, which was over-produced or induced by non-preferred carbon-sources, enhances the sensitivity toward antibiotics. Thus, controlled synthesis of CrcZ could provide a means to (re)sensitize P. aeruginosa to different classes of antibiotics.
Highlights
P. aeruginosa is a Gram-negative opportunistic pathogen that is associated with a broad spectrum of acute and chronic infections (Kerr and Snelling, 2009)
The largest differences were observed with cefepime and fosfomycin, which interfere with cell wall synthesis, and with gentamicin and tetracycline, which inhibit protein synthesis
As these growth-dependent assays could reflect the impact of the hfq deletion on the ability of the respective strains to grow and divide, we tested whether an increased susceptibility to an antibiotic is observed with PA14 hfq grown to early stationary phase
Summary
P. aeruginosa is a Gram-negative opportunistic pathogen that is associated with a broad spectrum of acute and chronic infections (Kerr and Snelling, 2009). Metabolic Regulation of Hfq-Dependent Antibiotic Susceptibility lifestyle is the signaling molecule cyclic-3′,5′-diguanylic acid (cdi-GMP) (Valentini and Filloux, 2016). Elevated levels of c-di-GMP can interfere with antibiotic resistance in a manner unrelated to biofilm growth (Hoffman et al, 2005; Gupta et al, 2013, 2014; Nicastro et al, 2014). In addition to the c-di-GMP signaling pathway, the Gac/Rsm network regulates the switch between planktonic and biofilm lifestyle (Mikkelsen et al, 2011). The levels of RsmZ are dependent on RNase G (CafA), the synthesis of which is controlled by the two component system BfiSR in a biofilm specific manner (Petrova and Sauer, 2010). RsmA and RsmN affect the synthesis of DGCs, like SiaD, RoeA and SadC at the posttranscriptional level (Moscoso et al, 2014; Romero et al, 2018)
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