Abstract
Efflux pumps of the resistance-nodulation-cell-division (RND) family increase antibiotic resistance in many bacterial pathogens, representing candidate targets for the development of antibiotic adjuvants. RND pumps have also been proposed to contribute to bacterial infection, implying that efflux pump inhibitors (EPIs) could also act as anti-virulence drugs. Nevertheless, EPIs are usually investigated only for their properties as antibiotic adjuvants, while their potential anti-virulence activity is seldom taken into account. In this study it is shown that RND efflux pumps contribute to Pseudomonas aeruginosa PAO1 pathogenicity in an insect model of infection, and that the well-characterized EPI Phe-Arg-β-naphthylamide (PAβN) is able to reduce in vivo virulence of the P. aeruginosa PAO1 laboratory strain, as well as of clinical isolates. The production of quorum sensing (QS) molecules and of QS-dependent virulence phenotypes is differentially affected by PAβN, depending on the strain. Transcriptomic and phenotypic analyses showed that the protection exerted by PAβN from P. aeruginosa PAO1 infection in vivo correlates with the down-regulation of key virulence genes (e.g. genes involved in iron and phosphate starvation). Since PAβN impacts P. aeruginosa virulence, anti-virulence properties of EPIs are worthy to be explored, taking into account possible strain-specificity of their activity.
Highlights
Introduction of any antibiotic in the clinical practice invariably results in ensuing resistance
The transcriptional profiles of P. aeruginosa PAO1 grown to an A600 of 2.5 in Lysogeny Broth (LB) in the presence or in the absence of 27 μM PAβN were compared by means of high-density oligonucleotide microarrays, by using
Both academic and industrial research is currently directed to the development of efflux inhibitors, and the interest in RND efflux pump inhibitors as antibiotic adjuvants is steadily increasing over the years[2, 5,6,7]
Summary
Introduction of any antibiotic in the clinical practice invariably results in ensuing resistance. Different from conventional antibiotics, adjuvants share the distinctive feature of targeting bacterial factors not essential for growth, such as virulence determinants (e.g. toxins, adhesins and tissue-degrading enzymes) or antibiotic resistance determinants (e.g. efflux pumps, antibiotic inactivating enzymes). Such treatments are aimed at facilitating host immune response and/or antibiotic action in clearing the infection. The resistance-nodulation-cell-division (RND) family of efflux pumps is considered a viable target for the development of drugs aimed at increasing bacterial susceptibility to antibiotics, due to their prominent contribution to the MDR phenotype and to the absence of human homologues[2, 5,6,7]. The P. aeruginosa genome is predicted to encode multiple RND efflux pumps, four of which are of clinical importance for MDR, namely MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY-OprM, and are frequently found to be up-regulated in clinical isolates[11]
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