Abstract
Quinolone resistance is usually due to mutations in the genes encoding bacterial topoisomerases. However, different reports have shown that neither clinical quinolone resistant isolates nor in vitro obtained Stenotrophomonas maltophilia mutants present mutations in such genes. The mechanisms so far described consist on efflux pumps’ overexpression. Our objective is to get information on novel mechanisms of S. maltophilia quinolone resistance. For this purpose, a transposon-insertion mutant library was obtained in S. maltophilia D457. One mutant presenting reduced susceptibility to nalidixic acid was selected. Inverse PCR showed that the inactivated gene encodes RNase G. Complementation of the mutant with wild-type RNase G allele restored the susceptibility to quinolones. Transcriptomic and real-time RT-PCR analyses showed that several genes encoding heat-shock response proteins were expressed at higher levels in the RNase defective mutant than in the wild-type strain. In agreement with this situation, heat-shock reduces the S. maltophilia susceptibility to quinolone. We can then conclude that the inactivation of the RNase G reduces the susceptibility of S. maltophilia to quinolones, most likely by regulating the expression of heat-shock response genes. Heat-shock induces a transient phenotype of quinolone resistance in S. maltophilia.
Highlights
Stenotrophomonas maltophilia is a nosocomial opportunistic pathogen that is considered a prototype of intrinsically resistant bacterium. (Brooke, 2012) The characteristic low-susceptibility of this organism to different antibiotics mainly relies in the presence in its genome of genes encoding several intrinsic resistance elements that include antibiotic-inactivating enzymes, multidrug efflux pumps and a quinolone resistance protein; SmQnr. (Walsh et al, 1997; Lambert et al, 1999; Alonso and Martinez, 2000; Avison et al, 2002; Okazaki and Avison, 2007; Crossman et al, 2008; Sanchez et al, 2008; Shimizu et al, 2008; Al-Hamad et al, 2009; Sanchez and Martinez, 2010; Garcia-Leon et al, 2014b) Quinolones are synthetic antimicrobials which targets are the bacterial topoisomerases
Differing to other organisms in which high-level quinolone resistance is usually due to mutations at the genes encoding the bacterial topoisomerases, this type of quinolone-resistance mutations have never been described neither in S. maltophilia clinical isolates nor in the case of in vitro selected quinolone resistant mutants of this bacterial species (Ribera et al, 2002; Valdezate et al, 2002; Garcia-Leon et al, 2014b)
While in some isolates quinolone resistance is associated to overexpression of multidrug efflux pumps (Alonso and Martinez, 2001; Sanchez et al, 2004; Garcia-Leon et al, 2015), some other mechanisms of resistance remain to be explored in this pathogen
Summary
Stenotrophomonas maltophilia is a nosocomial opportunistic pathogen that is considered a prototype of intrinsically resistant bacterium. (Brooke, 2012) The characteristic low-susceptibility of this organism to different antibiotics mainly relies in the presence in its genome of genes encoding several intrinsic resistance elements that include antibiotic-inactivating enzymes, multidrug efflux pumps and a quinolone resistance protein; SmQnr. (Walsh et al, 1997; Lambert et al, 1999; Alonso and Martinez, 2000; Avison et al, 2002; Okazaki and Avison, 2007; Crossman et al, 2008; Sanchez et al, 2008; Shimizu et al, 2008; Al-Hamad et al, 2009; Sanchez and Martinez, 2010; Garcia-Leon et al, 2014b) Quinolones are synthetic antimicrobials which targets are the bacterial topoisomerases. Some quinolone resistant clinical isolates neither overproduce any of the already described S. maltophilia multidrug efflux pumps not present mutations on the genes encoding bacterial topoisomerases (Garcia-Leon et al, 2014b, 2015) This indicates that there are still mechanisms of quinolone resistance, including overexpression of other efflux pumps as SmrA, which is known to extrude quinolones (Al-Hamad et al, 2009) that remain to be unveiled in S. maltophilia. The inactivation of RNases has been associated in few cases with changes in the susceptibility to antibiotics; in most published articles and opposite to our findings, such inactivation increases the susceptibility to the analyzed antimicrobials (Saramago et al, 2014)
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