The Efflux Pump SmeDEF Contributes to Trimethoprim-Sulfamethoxazole Resistance in Stenotrophomonas maltophilia

Abstract

Trimethoprim-sulfamethoxazole (co-trimoxazole) is one of the antimicrobials of choice for the treatment of Stenotrophomonas maltophilia infections. The analysis of mutants either lacking or overexpressing the efflux pump SmeDEF shows that this efflux pump contributes to intrinsic and acquired co-trimoxazole resistance in S. maltophilia. Since SmeDEF can extrude a variety of antibiotics, selection with such antimicrobials, including quinolones, might also select for S. maltophilia co-trimoxazole resistance.T he treatment of Stenotrophomonas maltophilia, an opportunistic pathogen involved in different nosocomial infections, is difficult, owing to its low level of susceptibility to several antibiotics and its capability to acquire further resistance during clinical treatment. The intrinsic resistance of this pathogen is mainly due to the presence in its genome of genes encoding different resistance determinants, as several multidrug resistance (MDR) efflux pumps and antibiotic-modifying enzymes, and the quinolone resistance gene Smqnr (1, 2). Acquired resistance is mediated by the acquisition of mobile genetic elements containing antibiotic resistance genes and by the overexpression of chromosomal resistance genes encoding efflux pumps due to mutations in genes encoding the local regulators of these determinants (3-5).The combination of antibiotics that inhibit enzymes of the folate biosynthesis pathway, trimethoprim and sulfamethoxazole (co-trimoxazole), is one of the choices for S. maltophilia treatment. In 2005, S. maltophilia represented only 4.7% of co-trimoxazole-resistant isolates (6), although this percentage varies geographically and has increased in the last few years. While from 1998 to 2008, only 14.6% of isolates in Taiwan were co-trimoxazole resistant, nowadays, this number has increased to 31.1% (7). The rationale behind the use of antimicrobial combinations is that the frequency of resistant mutants will be lower than that for single-target drugs, since mutations at the genes encoding both targets will be required in the case of combined drugs (8). We reasoned that bacteria could overcome this situation if one efflux pump is able to extrude both antimicrobials, since a single mutation will lead to the overexpression of the efflux pump and confer resistance. This possibility was suggested in Pseudomonas aeruginosa, because strains overexpressing oprM, the gene encoding the outer membrane protein of the mexAB efflux pump, were less susceptible to sulfamethoxazole and trimethoprim (9). In addition, the study of clinical S. maltophilia isolates has shown a weak correlation between co-trimoxazole resistance and overexpression of the MDR efflux pumps SmeDEF and SmeABC (10). The overexpression of the efflux pump SmeABC reduces susceptibility to aminoglycosides, ␤-lactams, and fluoroquinolones, but only the deletion of the smeC gene (outer membrane protein gene) has a direct effect on intrinsic resistance (11). The efflux pump Sme-DEF is responsible for intrinsic and acquired resistance to tetracycline, chl...

Overexpression of the Efflux Pumps SmeVWX and SmeDEF Is a Major Cause of Resistance to Co-trimoxazole in Stenotrophomonas maltophilia

“…SmeVWX is not involved in the intrinsic co-trimoxazole resistance of S. maltophilia. We have previously described that SmeDEF contributes to intrinsic and acquired co-trimoxazole resistance in S. maltophilia (18). The results presented in the current work indicate that SmeVWX, when overexpressed, is a relevant element in the acquisition of S. maltophilia co-trimoxazole resistance as well.…”

“…Indeed, different studies have shown that the activity of some efflux pumps might affect S. maltophilia co-trimoxazole susceptibility. Among these studies, it has been shown that the overexpression of SmeDEF reduces the susceptibility to co-trimoxazole of S. maltophilia, while the inactivation of this efflux pump increases the bacterial susceptibility to this antimicrobial (18). Other studies have shown that the deletion of the efflux pump SmeYZ or of the outer membrane protein TolC, the latter required for the activity of the efflux pump SmeOP, increases the susceptibility of S. maltophilia to co-trimoxazole (19)(20)(21).…”

Type II Secretion-Dependent Degradative and Cytotoxic Activities Mediated by Stenotrophomonas maltophilia Serine Proteases StmPr1 and StmPr2

“…Community-acquired S. maltophilia infections, especially in the high-risk populations mentioned, have been reported (5), and recently, a communityacquired skin infection was reported for the first time in an immunocompetent individual (6). The multidrug-resistant nature of S. maltophilia makes treatment of infections highly difficult (7), and in recent years, an increased resistance to the preferred antibiotic trimethoprim-sulfamethoxazole has been reported (8)(9)(10). These findings emphasize the need to better understand the virulence mechanisms employed by S. maltophilia.…”

Prolonged exposure of Stenotrophomonas maltophilia biofilms to trace levels of clofibric acid alters antimicrobial tolerance and virulence

“…The present results demonstrated that S. maltophilia was resistant to AMO, OXA and SPE, even without being exposed to CA (Table 2). S. maltophilia is commonly described as an opportunistic pathogen with intrinsic multidrug-resistance (Zhang et al, 2000;S anchez, 2015;Adegoke et al, 2017;Rizek et al, 2018). However, it is also known that S. maltophilia can acquire resistance (Song et al, 2010;Furlan et al, 2018;Rizek et al, 2018).…”

“…It is important to emphasize that the concentrations used in that study are the therapeutic doses (CA e 28.6 mg/kg/d, EA e 2.9 mg/kg/d and 2,4-D e 70 mg/kg/d) which are significantly higher than the trace concentrations detected in environment (170e17000 ng/L). TMP-SMX is the most common therapeutic option used to treat S. maltophilia infections (Emblidge and DeLorenzo, 2006;S anchez and Martínez, 2015) and tolerance to this combination of antibiotics was not observed despite the exposure of S. maltophilia to CA.…”