Abstract
Pseudomonas aeruginosa can cause life-threatening infections in immunocompromised patients. The first-line agents to treat P. aeruginosa infections are carbapenems. However, the emergence of carbapenem-resistant P. aeruginosa strains greatly compromised the effectiveness of carbapenem treatment, which makes the surveillance on their spreading and transmission important. Here we characterized the full-length genomes of two carbapenem-resistant P. aeruginosa clinical isolates that are capable of producing New Delhi metallo-β-lactamase-1 (NDM-1). We show that blaNDM-1 is carried by a novel integrative and conjugative element (ICE) ICETn43716385, which also carries the macrolide resistance gene msr(E) and the florfenicol resistance gene floR. By exogenously expressing msr(E) in P. aeruginosa laboratory strains, we show that Msr(E) can abolish azithromycin-mediated quorum sensing inhibition in vitro and anti-Pseudomonas effect in vivo. We conclude that ICEs are important in transmitting carbapenem resistance, and that anti-virulence treatment of P. aeruginosa infections using sub-inhibitory concentrations of macrolides can be challenged by horizontal gene transfer.
Highlights
Pseudomonas aeruginosa can cause life-threatening infections in immunocompromised patients
We found that the 11 genomes are highly similar to each other as shown by multiple genome alignment (Supplementary Fig. 1) and carried the same sets of antibiotic resistance genes, suggesting that the 11 New Delhi metallo-βlactamase-1 (NDM-1)-producing P. aeruginosa strains isolated in this outbreak belong to the same phylogenetic group
The results showed that 8 μg/mL of AZM (1/32 of the AZM minimal inhibitory concentration (MIC) of PAO1) reduced elastase production in both wildtype PAO1 and vector-carrying strain PAO1/pUCP18 by at least 40%, whereas the elastase produced by PAO1/pUCP18::msr(E) was not significantly affected upon AZM treatment (Fig. 4a)
Summary
Pseudomonas aeruginosa can cause life-threatening infections in immunocompromised patients. Pseudomonas aeruginosa is an opportunistic pathogen which can cause life-threatening infections in immunocompromised patients[1] It is responsible for chronic wound infections, ventilator-associated pneumonia and chronic airway infections in cystic fibrosis and chronic obstructive pulmonary disease patients[2,3,4,5,6]. The NDM-1-producing P. aeruginosa strains usually have high resistance to carbapenems, as well as multidrug resistance to other antibiotics, which leaves only a handful of antibiotics effective to treat their infections in clinical practice[10,11,12,13,14,15,16]. The macrolide antibiotics such as erythromycin, azithromycin (AZM) and clarithromycin were shown to have a promising antiquorum sensing activity, which makes them ideal anti-virulence drugs for treating P. aeruginosa infections[21]. The use of macrolides as quorum sensing inhibitors has expanded our antimicrobial arsenal against P. aeruginosa infections until new and more efficient anti-virulence drugs become clinically available
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