Quinolone antimicrobials are synthetic and widely used in clinical medicine Resistance emerged with clinical use and became common in some bacterial pathogens Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s) These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes Mutations of both types can accumulate with selection pressure and produce highly resistant strains Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones Thus, the bacterial quinolone resistance armamentarium is large

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Mechanisms of drug resistance: quinolone resistance.

Three mechanisms for plasmid-mediated quinolone resistance (PMQR) have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from chromosomal genes in aquatic bacteria, are usually associated with mobilizing or transposable elements on plasmids, and are often incorporated into sul1-type integrons. The second plasmid-mediated mechanism involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common aminoglycoside acetyltransferase AAC(6′)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher-level resistance and makes infection by pathogens containing PMQR harder to treat.

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Plasmid-Mediated Quinolone Resistance

Stenotrophomonas maltophilia is a commensal and an emerging pathogen earlier noted in broad-spectrum life threatening infections among the vulnerable, but more recently as a pathogen in immunocompetent individuals. The bacteria are consistently being implicated in necrotizing otitis, cutaneous infections including soft tissue infection and keratitis, endocarditis, meningitis, acute respiratory tract infection (RTI), bacteraemia (with/without hematological malignancies), tropical pyomyositis, cystic fibrosis, septic arthritis, among others. S. maltophilia is also an environmental bacteria occurring in water, rhizospheres, as part of the animals' microflora, in foods, and several other microbiota. This review highlights clinical reports on S. maltophilia both as an opportunistic and as true pathogen. Also, biofilm formation as well as quorum sensing, extracellular enzymes, flagella, pili/fimbriae, small colony variant, other virulence or virulence-associated factors, the antibiotic resistance factors, and their implications are considered. Low outer membrane permeability, natural MDR efflux systems, and/or resistance genes, resistance mechanisms like the production of two inducible chromosomally encoded β-lactamases, and lack of carefully compiled patient history are factors that pose great challenges to the S. maltophilia control arsenals. The fluoroquinolone, some tetracycline derivatives and trimethoprim-sulphamethaxole (TMP-SMX) were reported as effective antibiotics with good therapeutic outcome. However, TMP-SMX resistance and allergies to sulfa together with high toxicity of fluoroquinolone are notable setbacks. S. maltophilia's production and sustenance of biofilm by quorum sensing enhance their virulence, resistance to antibiotics and gene transfer, making quorum quenching an imperative step in Stenotrophomonas control. Incorporating several other proven approaches like bioengineered bacteriophage therapy, Epigallocatechin-3-gallate (EGCG), essential oil, nanoemulsions, and use of cationic compounds are promising alternatives which can be incorporated in Stenotrophomonas control arsenal.

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Stenotrophomonas maltophilia as an emerging ubiquitous pathogen: Looking beyond contemporary antibiotic therapy

The emergence of clinical resistance to tigecycline

The aim of this study was to detect novel variants of the Stenotrophomonas maltophilia
Smqnr gene family and analyse the prevalence of Smqnr genes in clinical isolates of S. maltophilia in China. In total, 442 clinical isolates of S. maltophilia were collected from nine hospitals in four provinces in China. Antimicrobial susceptibility testing against six commonly used antibiotics was performed on these isolates. The sequences of the Smqnr genes amplified by PCR were aligned with those of known Smqnr genes in GenBank and an Smqnr database. The resistance rate against co-trimoxazole was highest at 48.6 %, followed by resistance rates against ceftazidime, chloramphenicol, ticarcillin/clavulanate and tigecycline at 28.7, 21.3, 19.0 and 16.1 %, respectively. The highest susceptibility was shown to levofloxacin, with a resistance rate of just 6.1 %. Smqnr genes were detected in 114 isolates, and comprised 11 previously identified genes and 20 new variants, bringing the total number of known Smqnr genes to 47. The 20 novel Smqnr genes were designated Smqnr28–47 and the encoded proteins showed only 1–12 amino acid differences among each other. The most common Smqnr genes in China were Smqnr8 and its variant Smqnr35 with prevalences of 17.5 % (20/114) and 13.2 % (15/114), respectively. Both the known and the novel Smqnr genes were discovered in both quinolone non-sensitive and sensitive isolates with similar frequency, suggesting that the Smqnr gene makes little contribution to quinolone resistance in this organism.

Qiang Shen

Papers

Detection of the Smqnr quinolone protection gene and its prevalence in clinical isolates of Stenotrophomonas maltophilia in China.