scholarly journals The Inactivation of Intrinsic Antibiotic Resistance Determinants Widens the Mutant Selection Window for Quinolones in Stenotrophomonas maltophilia

2012 ◽  
Vol 56 (12) ◽  
pp. 6397-6399 ◽  
Author(s):  
Guillermo García-León ◽  
María B. Sánchez ◽  
José L. Martínez
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Wild Type Strain ◽  
Efflux Pump ◽  
Intrinsic Resistance ◽  
Mutant Selection ◽  
Content Type ◽  
Resistance Determinants ◽  
Selection Window ◽  
Resistance Protein ◽  
Resistant Mutants

ABSTRACTWe have determined that the mutational inactivation of the SmeDEF efflux pump and the SmQnr quinolone resistance protein widens the mutant selection windows for ofloxacin and ciprofloxacin ofStenotrophomonas maltophiliaby reducing their MICs. Resistant mutants arising from a strain lacking SmeDEF and SmQnr presented levels of susceptibility similar to those of the wild-type strain. This indicates that inactivation of intrinsic resistance determinants might increase the chances for selecting resistant mutants at low antibiotic concentrations.

scholarly journals Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by UsingIn VitroDynamic Models

2015 ◽  
Vol 60 (3) ◽  
pp. 1208-1215 ◽  
Author(s):  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Andrey V. Romanov ◽  
Mikhail V. Edelstein ◽  
Stephen H. Zinner ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Mutant Selection ◽  
Content Type ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Ciprofloxacin Resistance ◽  
Resistant Mutants ◽  
Time Courses ◽  
Selection Of

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of threeKlebsiella pneumoniaestrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantK. pneumoniaemutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistantK. pneumoniae(AUBCM) were bell shaped. These relationships predict highly variable “antimutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor ofK. pneumoniaeresistance is lower than that of the AUC24/MIC ratio.

scholarly journals Involvement of Efflux Pumps in the Resistance to Peptidoglycan Synthesis Inhibitors in Mycobacterium tuberculosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1941-1943 ◽  
Author(s):  
Neela Dinesh ◽  
Sreevalli Sharma ◽  
Meenakshi Balganesh
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type Strain ◽  
Wild Type Strain ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Wild Type ◽  
Intrinsic Resistance ◽  
Content Type ◽  
Peptidoglycan Synthesis

ABSTRACTWe evaluated the contributions ofMycobacterium tuberculosisefflux pumps towards intrinsic resistance to different classes of peptidoglycan synthesis inhibitors (PSI). Our study indicates that the efflux pump knockout strains are more susceptible to PSI than the wild type. Vancomycin and ceftriaxone exhibited up to 3 log increased kill on efflux pump mutants compared to the wild-type strain, strongly suggesting an important role for efflux pumps in the intrinsic resistance ofM. tuberculosisto PSI.

scholarly journals Overexpression of the Efflux Pumps SmeVWX and SmeDEF Is a Major Cause of Resistance to Co-trimoxazole inStenotrophomonas maltophilia

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
María Blanca Sánchez ◽  
José Luis Martínez
Keyword(s):  
Molecular Epidemiology ◽  
Drug Combination ◽  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Efflux Pumps ◽  
Content Type ◽  
Resistant Mutants ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACTCo-trimoxazole is one of the antimicrobials of choice for treatingStenotrophomonas maltophiliainfections. Most works on the molecular epidemiology of the resistance to this drug combination are based on the analysis ofsulgenes. Nevertheless, the existence of clinical co-trimoxazole-resistantS. maltophiliaisolates that do not harborsulgenes has been reported. To investigate potential mutations that can reduce the susceptibility ofS. maltophiliato co-trimoxazole, spontaneousS. maltophiliaco-trimoxazole-resistant mutants isolated under different co-trimoxazole concentrations were studied. All mutants presented phenotypes compatible with the overexpression of either SmeVWX (94.6%) or SmeDEF (5.4%). Indeed, the analysis of a selected set of strains showed that the overexpression of either of these efflux pumps, which was due to mutations in their regulatorssmeRvandsmeT, respectively, was the cause of co-trimoxazole resistance. No other efflux pump was overexpressed in any of the studied mutants, indicating that they do not participate in the observed resistance phenotype. The analysis of mutants overexpressing or lacking SmeDEF or SmeVWX shows that SmeDEF contributes to the intrinsic and acquired resistance to co-trimoxazole inS. maltophilia, whereas SmeVWX only contributes to acquired resistance. It is important to highlight that all mutants were less susceptible to other antibiotics, including chloramphenicol and quinolones. Since both SmeVWX and SmeDEF are major determinants of quinolone resistance, the potential cross-selection of resistance to co-trimoxazole and quinolones, when either of the antimicrobials is used, is of particular concern for the treatment ofS. maltophiliainfections.

scholarly journals Novel Mechanisms of Efflux-Mediated Levofloxacin Resistance and Reduced Amikacin Susceptibility in Stenotrophomonas maltophilia

2020 ◽  
Vol 65 (1) ◽  
pp. e01284-20
Author(s):  
Punyawee Dulyayangkul ◽  
Karina Calvopiña ◽  
Kate J. Heesom ◽  
Matthew B. Avison
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Regulatory System ◽  
Fluoroquinolone Resistance ◽  
Content Type ◽  
Antimicrobial Drug Resistance ◽  
Regulatory Systems ◽  
Selection Of

ABSTRACTFluoroquinolone resistance in Stenotrophomonas maltophilia is multifactorial, but the most significant factor is overproduction of efflux pumps, particularly SmeDEF, following mutation. Here, we report that mutations in the glycosyl transferase gene smlt0622 in S. maltophilia K279a mutant K M6 cause constitutive activation of SmeDEF production, leading to elevated levofloxacin MIC. Selection of a levofloxacin-resistant K M6 derivative, K M6 LEVr, allowed identification of a novel two-component regulatory system, Smlt2645/6 (renamed SmaRS). The sensor kinase Smlt2646 (SmaS) is activated by mutation in K M6 LEVr causing overproduction of two novel ABC transporters and the known aminoglycoside efflux pump SmeYZ. Overproduction of one ABC transporter, Smlt1651-4 (renamed SmaCDEF), causes levofloxacin resistance in K M6 LEVr. Overproduction of the other ABC transporter, Smlt2642/3 (renamed SmaAB), and SmeYZ both contribute to the elevated amikacin MIC against K M6 LEVr. Accordingly, we have identified two novel ABC transporters associated with antimicrobial drug resistance in S. maltophilia and two novel regulatory systems whose mutation causes resistance to levofloxacin, clinically important as a promising drug for monotherapy against this highly resistant pathogen.

scholarly journals Contribution of Resistance-Nodulation-Division Efflux Pump OperonsmeU1-V-W-U2-Xto Multidrug Resistance of Stenotrophomonas maltophilia

2011 ◽  
Vol 55 (12) ◽  
pp. 5826-5833 ◽  
Author(s):  
Chao-Hsien Chen ◽  
Chiang-Ching Huang ◽  
Tsao-Chuen Chung ◽  
Rouh-Mei Hu ◽  
Yi-Wei Huang ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Type Systems ◽  
Resistant Mutant ◽  
Multidrug Resistant ◽  
Content Type ◽  
Membrane Fusion Protein ◽  
Resistance Nodulation Division

ABSTRACTKJ09C, a multidrug-resistant mutant ofStenotrophomonas maltophiliaKJ, was generated byin vitroselection with chloramphenicol. The multidrug-resistant phenotype of KJ09C was attributed to overexpression of a resistance nodulation division (RND)-type efflux system encoded by an operon consisting of five genes:smeU1,smeV,smeW,smeU2, andsmeX. Proteins encoded bysmeV,smeW, andsmeXwere similar to the membrane fusion protein, RND transporter, and outer membrane protein, respectively, of known RND-type systems. The proteins encoded bysmeU1andsmeU2were found to belong to the family of short-chain dehydrogenases/reductases. Mutant KJ09C exhibited increased resistance to chloramphenicol, quinolones, and tetracyclines and susceptibility to aminoglycosides; susceptibility to β-lactams and erythromycin was not affected. The expression of thesmeU1-V-W-U2-Xoperon was regulated by the divergently transcribed LysR-type regulator genesmeRv. Overexpression of the SmeVWX pump contributed to the acquired resistance to chloramphenicol, quinolones, and tetracyclines. Inactivation ofsmeVandsmeWcompletely abolished the activity of the SmeVWX pump, whereas inactivation ofsmeXalone decreased the activity of the SmeVWX pump. The enhanced aminoglycoside susceptibility observed in KJ09C resulted from SmeX overexpression.

scholarly journals Transcriptional Profiling of Mycobacterium tuberculosis Exposed toIn VitroLysosomal Stress

2016 ◽  
Vol 84 (9) ◽  
pp. 2505-2523 ◽  
Author(s):  
Wenwei Lin ◽  
Paola Florez de Sessions ◽  
Garrett Hor Keong Teoh ◽  
Ahmad Naim Nazri Mohamed ◽  
Yuan O. Zhu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Metabolic Reprogramming ◽  
Human Macrophage ◽  
Host Immune System ◽  
Activated Macrophages ◽  
Intrinsic Resistance ◽  
Macrophage Infection ◽  
Content Type

Increasing experimental evidence supports the idea thatMycobacterium tuberculosishas evolved strategies to survive within lysosomes of activated macrophages. To further our knowledge ofM. tuberculosisresponse to the hostile lysosomal environment, we profiled the global transcriptional activity ofM. tuberculosiswhen exposed to the lysosomal soluble fraction (SF) prepared from activated macrophages. Transcriptome sequencing (RNA-seq) analysis was performed using various incubation conditions, ranging from noninhibitory to cidal based on the mycobacterial replication or killing profile. Under inhibitory conditions that led to the absence of apparent mycobacterial replication,M. tuberculosisexpressed a unique transcriptome with modulation of genes involved in general stress response, metabolic reprogramming, respiration, oxidative stress, dormancy response, and virulence. The transcription pattern also indicates characteristic cell wall remodeling with the possible outcomes of increased infectivity, intrinsic resistance to antibiotics, and subversion of the host immune system. Among the lysosome-specific responses, we identified theglgE-mediated 1,4 α-glucan synthesis pathway and a defined group of VapBC toxin/anti-toxin systems, both of which represent toxicity mechanisms that potentially can be exploited for killing intracellular mycobacteria. A meta-analysis including previously reported transcriptomic studies in macrophage infection andin vitrostress models was conducted to identify overlapping and nonoverlapping pathways. Finally, the Tap efflux pump-encoding geneRv1258cwas selected for validation. AnM. tuberculosis ΔRv1258cmutant was constructed and displayed increased susceptibility to killing by lysosomal SF and the antimicrobial peptide LL-37, as well as attenuated survival in primary murine macrophages and human macrophage cell line THP-1.

scholarly journals Influence of Inoculum Size on the Selection of Resistant Mutants of Escherichia coli in Relation to Mutant Prevention Concentrations of Marbofloxacin

2007 ◽  
Vol 51 (11) ◽  
pp. 4163-4166 ◽  
Author(s):  
Aude Ferran ◽  
Véronique Dupouy ◽  
Pierre-Louis Toutain ◽  
Alain Bousquet-Mélou
Keyword(s):  
Escherichia Coli ◽  
Bacterial Population ◽  
Inoculum Size ◽  
Pharmacodynamic Model ◽  
Initial Size ◽  
Mutant Selection ◽  
Selection Window ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT We demonstrate using an in vitro pharmacodynamic model that the likelihood of selection of Escherichia coli mutants resistant to a fluoroquinolone was increased when the initial size of the bacterial population, exposed to fluoroquinolone concentrations within the mutant selection window, was increased.

scholarly journals Synergistic Combination of Linezolid and Fosfomycin Closing Each Other’s Mutant Selection Window to Prevent Enterococcal Resistance

2021 ◽  
Vol 11 ◽  
Author(s):  
Lifang Jiang ◽  
Na Xie ◽  
Mingtao Chen ◽  
Yanyan Liu ◽  
Shuaishuai Wang ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Bacterial Resistance ◽  
Selection Index ◽  
Resistance Mechanism ◽  
Mutant Selection ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Synergistic Combination ◽  
Selection Of

Enterococci, the main pathogens associated with nosocomial infections, are resistant to many common antibacterial drugs including β-lactams, aminoglycosides, etc. Combination therapy is considered an effective way to prevent bacterial resistance. Preliminary studies in our group have shown that linezolid combined with fosfomycin has synergistic or additive antibacterial activity against enterococci, while the ability of the combination to prevent resistance remains unknown. In this study, we determined mutant prevention concentration (MPC) and mutant selection window (MSW) of linezolid, fosfomycin alone and in combination including different proportions for five clinical isolates of Enterococcus and characterized the resistance mechanism for resistant mutants. The results indicated that different proportions of linezolid combined with fosfomycin had presented different MPCs and MSWs. Compared with linezolid or fosfomycin alone, the combination can restrict the enrichment of resistant mutants at a lower concentration. A rough positive correlation between the selection index (SI) of the two agents in combination and the fractional inhibitory concentration index (FICI) of the combination displayed that the smaller FICI of linezolid and fosfomycin, the more probable their MSWs were to close each other. Mutations in ribosomal proteins (L3 and L4) were the mechanisms for linezolid resistant mutants. Among the fosfomycin-resistant mutants, only two strains have detected the MurA gene mutation related to fosfomycin resistance. In conclusion, the synergistic combination of linezolid and fosfomycin closing each other’s MSW could effectively suppress the selection of enterococcus resistant mutants, suggesting that the combination may be an alternative for preventing enterococcal resistance. In this study, the resistance mechanism of fosfomycin remains to be further studied.

scholarly journals The Efflux Pump MexXY/OprM Contributes to the Tolerance and Acquired Resistance of Pseudomonas aeruginosa to Colistin

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Hélène Puja ◽  
Arnaud Bolard ◽  
Aurélie Noguès ◽  
Patrick Plésiat ◽  
Katy Jeannot
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Lipid A ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Intrinsic Resistance ◽  
Drug Induced ◽  
Functional Link ◽  
Content Type ◽  
Regulatory Systems ◽  
Early Drug

ABSTRACT The intrinsic resistance of Pseudomonas aeruginosa to polymyxins in part relies on the addition of 4-amino-4-deoxy-l-arabinose (Ara4N) molecules to the lipid A of lipopolysaccharide (LPS), through induction of operon arnBCADTEF-ugd (arn) expression. As demonstrated previously, at least three two-component regulatory systems (PmrAB, ParRS, and CprRS) are able to upregulate this operon when bacteria are exposed to colistin. In the present study, gene deletion experiments with the bioluminescent strain PAO1::lux showed that ParRS is a key element in the tolerance of P. aeruginosa to this last-resort antibiotic (i.e., resistance to early drug killing). Other loci of the ParR regulon, such as those encoding the efflux proteins MexXY (mexXY), the polyamine biosynthetic pathway PA4773-PA4774-PA4775, and Ara4N LPS modification process (arnBCADTEF-ugd), also contribute to the bacterial tolerance in an intricate way with ParRS. Furthermore, we found that both stable upregulation of the arn operon and drug-induced ParRS-dependent overexpression of the mexXY genes accounted for the elevated resistance of pmrB mutants to colistin. Deletion of the mexXY genes in a constitutively activated ParR mutant of PAO1 was associated with significantly increased expression of the genes arnA, PA4773, and pmrA in the absence of colistin exposure, thereby highlighting a functional link between the MexXY/OprM pump, the PA4773-PA4774-PA4775 pathway, and Ara4N-based modification of LPS. The role played by MexXY/OprM in the adaptation of P. aeruginosa to polymyxins opens new perspectives for restoring the susceptibility of resistant mutants through the use of efflux inhibitors.

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