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Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

Sanglard, Dominique; Ischer, Francoise; Bille, Jacques
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /04/2001 Português
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Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation of CgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, called CgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2 suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml...

In Vitro Activities of Six Quinolones and Mechanisms of Resistance in Staphylococcus aureus and Coagulase-Negative Staphylococci

Linde, Hans-Jörg; Schmidt, Mario; Fuchs, Emmi; Reischl, Udo; Niller, Hans-Helmut; Lehn, Norbert
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2001 Português
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Of 94 clinical isolates of Staphylococcus aureus (n = 51) and coagulase-negative staphylococci (CNS) (n = 43), mutations in the quinolone resistance-determining region of topoisomerases GrlA, GrlB, GyrA, and GyrB together with MICs of six quinolones were analyzed. Amino acid substitutions at identical residues (GrlA residues 80 and 84; GyrA residues 84 and 88) were found in S. aureus and CNS. Active efflux, as suggested by blocking by reserpine, contributed substantially to the resistance phenotype in some strains. Among ciprofloxacin, clinafloxacin, levofloxacin, nalidixic acid, trovafloxacin, and sparfloxacin, a 0.5-μg/ml concentration of sparfloxacin discriminated best between strains with two or three mutations and those with no mutations.

Development of Resistance to Ciprofloxacin, Rifampin, and Mupirocin in Methicillin-Susceptible and -Resistant Staphylococcus aureus Isolates

Schmitz, Franz-Josef; Fluit, Ad C.; Hafner, Dieter; Beeck, Andreas; Perdikouli, Mirella; Boos, Mechthild; Scheuring, Sybille; Verhoef, Jan; Köhrer, Karl; Von Eiff, Christof
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2000 Português
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A relationship between resistance to methicillin and resistance to fluoroquinolones, rifampin, and mupirocin has been described for Staphylococcus aureus. Differences in resistance rates may be explainable by a higher spontaneous mutation rate (MR) or a faster development of resistance (DIFF) in methicillin-resistant S. aureus (MRSA). No differences in MR, DIFF, and mutations in grlA and gyrA were detected between methicillin-susceptible S. aureus and MRSA. The higher resistance rates in MRSA are not the result of hypermutability of target genes or a faster emergence of different mutations and may be the consequence of clonal spread of multiresistant MRSA.

Site-Specific Mutations in the 23S rRNA Gene of Helicobacter pylori Confer Two Types of Resistance to Macrolide-Lincosamide-Streptogramin B Antibiotics

Wang, Ge; Taylor, Diane E.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/1998 Português
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Clarithromycin resistance in Helicobacter pylori is mainly due to A-to-G mutations within the peptidyltransferase region of the 23S rRNA. In the present study, cross-resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics (MLS phenotypes) has been investigated for several clinical isolates of H. pylori. Two major types of MLS resistance were identified and correlated with specific point mutations in the 23S rRNA gene. The A2142G mutation was linked with high-level cross-resistance to all MLS antibiotics (type I), and the A2143G mutation gave rise to an intermediate level of resistance to clarithromycin and clindamycin but no resistance to streptogramin B (type II). In addition, streptogramin A and streptogramin B were demonstrated to have a synergistic effect on both MLS-sensitive and MLS-resistant H. pylori strains. To further understand the mechanism of MLS resistance in H. pylori, we performed in vitro site-directed mutagenesis (substitution of G, C, or T for A at either position 2142 or 2143 of the 23S rRNA gene). The site-directed point mutations were introduced into a clarithromycin-susceptible strain, H. pylori UA802, by natural transformation followed by characterization of their effects on MLS resistance in an isogenic background. Strains with A-to-G and A-to-C mutations at the same position within the 23S rRNA gene had similar levels of clarithromycin resistance...

Diversity of Ribosomal Mutations Conferring Resistance to Macrolides, Clindamycin, Streptogramin, and Telithromycin in Streptococcus pneumoniae

Canu, Annie; Malbruny, Brigitte; Coquemont, Maëlle; Davies, Todd A.; Appelbaum, Peter C.; Leclercq, Roland
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2002 Português
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Mechanisms of resistance were studied in 22 macrolide-resistant mutants selected in vitro from 5 parental strains of macrolide-susceptible Streptococcus pneumoniae by serial passage in various macrolides (T. A. Davies, B. E. Dewasse, M. R. Jacobs, and P. C. Appelbaum, Antimicrob. Agents Chemother., 44:414–417, 2000). Portions of genes encoding ribosomal proteins L22 and L4 and 23S rRNA (domains II and V) were amplified by PCR and analyzed by single-strand conformational polymorphism analysis to screen for mutations. The DNA sequences of amplicons from mutants that differed from those of parental strains by their electrophoretic migration profiles were determined. In six mutants, point mutations were detected in the L22 gene (G95D, P99Q, A93E, P91S, and G83E). The only mutant selected by telithromycin (for which the MIC increased from 0.008 to 0.25 μg/ml) contained a combination of three mutations in the L22 gene (A93E, P91S, and G83E). L22 mutations were combined with an L4 mutation (G71R) in one strain and with a 23S rRNA mutation (C2611A) in another strain. Nine other strains selected by various macrolides had A2058G (n = 1), A2058U (n = 2), A2059G (n = 1), C2610U (n = 1), and C2611U (n = 4) mutations (Escherichia coli numbering) in domain V of 23S rRNA. One mutant selected by clarithromycin and resistant to all macrolides tested (MIC...

Evolution of Resistance to Sulfadoxine-Pyrimethamine in Plasmodium falciparum

Gatton, Michelle L.; Martin, Laura B; Cheng, Qin
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/2004 Português
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76.79627%
The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosage, time of treatment, and drug elimination half-life, with an in-host dynamics model of P. falciparum malaria in a malaria-naïve host. The results indicate that the development of drug resistance can be categorized into three stages. The first is the selection of existing parasites with genetic mutations in the dihydrofolate reductase or dihydropteroate synthetase gene. This selection is driven by the long half-life of the sulfadoxine-pyrimethamine combination. The second stage involves the selection of parasites with allelic types of higher resistance within the host during an infection. The timing of treatment relative to initiation of a specific anti-P. falciparum EMP1 immune response is an important factor during this stage, as is the treatment dosage. During the third stage...

Mechanisms of Resistance in Multiple-Antibiotic-Resistant Escherichia coli Strains of Human, Animal, and Food Origins

Sáenz, Yolanda; Briñas, Laura; Domínguez, Elena; Ruiz, Joaquim; Zarazaga, Myriam; Vila, Jordi; Torres, Carmen
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /10/2004 Português
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Seventeen multiple-antibiotic-resistant nonpathogenic Escherichia coli strains of human, animal, and food origins showed a wide variety of antibiotic resistance genes, many of them carried by class 1 and class 2 integrons. Amino acid changes in MarR and mutations in marO were identified for 15 and 14 E. coli strains, respectively.

Molecular Analysis of Resistance to Streptogramin A Compounds Conferred by the Vga Proteins of Staphylococci

Chesneau, Olivier; Ligeret, Heidi; Hosan-Aghaie, Negin; Morvan, Anne; Dassa, Elie
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2005 Português
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The Vga and Msr resistance determinants, encoded by mobile genetic elements in various staphylococcal strains, belong to a family of ATP-binding cassette (ABC) proteins whose functions and structures are ill defined. Their amino acid sequences are similar to those of proteins involved in the immunity of streptomycetes to the macrolide-lincosamide-streptogramin antibiotics that they produce. Sequence analysis of the genomes of the gram-positive bacteria with low G+C contents revealed that Lmo0919 from Listeria monocytogenes is more closely related to Vga variants than to Msr variants. In the present study we compared the antibiotic resistance profiles conferred by the Vga-like proteins in two staphylococcal hosts. It was shown that Vga(A), the Vga(A) variant [Vga(A)v], and Lmo0919 can confer resistance to lincosamides and streptogramin A compounds, while only Vga(B) is able to increase the level of resistance to pristinamycin, a mixture of streptogramin A and streptogramin B compounds. By using polyclonal antibodies, we found that the Vga(A) protein colocalized with the β subunit of the F1-F0 ATPase in the membrane fractions of staphylococcal cells. In order to identify functional units in these atypical ABC proteins, such as regions that might be involved in substrate specificity and/or membrane targeting...

Emergence of Resistance to Rifampin and Rifalazil in Chlamydophila pneumoniae and Chlamydia trachomatis

Kutlin, Andrei; Kohlhoff, Stephan; Roblin, Patricia; Hammerschlag, Margaret R.; Riska, Paul
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2005 Português
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Although rifamycins have excellent activity against Chlamydophila pneumoniae and Chlamydia trachomatis in vitro, concerns about the possible development of resistance during therapy have discouraged their use for treatment of chlamydial infections. Rifalazil, a new semisynthetic rifamycin with a long half-life, is the most active antimicrobial against C. pneumoniae and C. trachomatis in vitro, indicating its potential for treatment of acute and chronic C. pneumoniae and C. trachomatis infections. We investigated the effect of serial passage of two C. pneumoniae isolates and two serotypes of C. trachomatis in subinhibitory concentrations of rifalazil and rifampin on the development of phenotypic and genotypic resistance. C. trachomatis developed resistance to both antimicrobials within six passages, with higher level resistance to rifampin (128 to 256 μg/ml) and lower level resistance to rifalazil (0.5 to 1 μg/ml). C. pneumoniae TW-183 developed only low-level resistance to rifampin (0.25 μg/ml) and rifalazil (0.016 μg/ml) after 12 passages. C. pneumoniae CWL-029 failed to develop resistance to either drug. Two unique mutations emerged in the rpoB gene of rifampin (L456I) and rifalazil (D461E)-resistant C. pneumoniae TW-183. A single mutation (H471Y) was detected in both rifampin- and rifalazil-resistant C. trachomatis UW-3/Cx/D...

In Vitro Infection Model Characterizing the Effect of Efflux Pump Inhibition on Prevention of Resistance to Levofloxacin and Ciprofloxacin in Streptococcus pneumoniae▿

Louie, Arnold; Brown, David L.; Liu, Weiguo; Kulawy, Robert W.; Deziel, Mark R.; Drusano, George L.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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The prevalence of fluoroquinolone-resistant Streptococcus pneumoniae is slowly rising as a consequence of the increased use of fluoroquinolone antibiotics to treat community-acquired pneumonia. We tested the hypothesis that increased efflux pump (EP) expression by S. pneumoniae may facilitate the emergence of fluoroquinolone resistance. By using an in vitro pharmacodynamic infection system, a wild-type S. pneumoniae strain (Spn-058) and an isogenic strain with EP overexpression (Spn-RC2) were treated for 10 days with ciprofloxacin or levofloxacin in the presence or absence of the EP inhibitor reserpine to evaluate the effect of EP inhibition on the emergence of resistance. Cultures of Spn-058 and Spn-RC2 were exposed to concentration-time profiles simulating those in humans treated with a regimen of ciprofloxacin at 750 mg orally once every 12 h and with regimens of levofloxacin at 500 and 750 mg orally once daily (QD; with or without continuous infusions of 20 μg of reserpine/ml). The MICs of ciprofloxacin and levofloxacin for Spn-058 were both 1 μg/ml when susceptibility testing was conducted with each antibiotic alone and with each antibiotic in the presence of reserpine. For Spn-RC2, the MIC of levofloxacin alone and with reserpine was also 1 μg/ml; the MICs of ciprofloxacin were 2 and 1 μg/ml...

Mechanisms of Resistance to Daptomycin in Enterococcus faecium▿

Montero, Clemente I.; Stock, Frida; Murray, Patrick R.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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In this study, we investigated the clonal emergence of daptomycin-resistant Enterococcus faecium strains isolated from a patient with leukocyte adhesion deficiency syndrome. The resistance mechanism in these strains is independent of either equivalent point mutations previously described for Staphylococcus aureus or daptomycin inactivation mechanisms identified in soil bacteria.

Molecular Mechanisms of Macrolide Resistance in Clinical Isolates of Mycoplasma pneumoniae from China▿

Xin, Deli; Mi, Zuhuang; Han, Xu; Qin, Ling; Li, Jing; Wei, Tianli; Chen, Xiaogeng; Ma, Shaojie; Hou, Ancun; Li, Gui; Shi, Dawei
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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Fifty clinical Mycoplasma pneumoniae strains were isolated from 370 children with respiratory tract infections. Four strains were susceptible to macrolides, while the other 46 (92%) were macrolide resistant. The molecular mechanism of resistance was shown to be associated with point mutations in 23S rRNA at positions 2063 and 2064.

Selection of Known Plasmodium falciparum Resistance-Mediating Polymorphisms by Artemether-Lumefantrine and Amodiaquine- Sulfadoxine-Pyrimethamine but Not Dihydroartemisinin- Piperaquine in Burkina Faso▿

Somé, Anyirékun Fabrice; Séré, Yves Y.; Dokomajilar, Christian; Zongo, Issaka; Rouamba, Noël; Greenhouse, Bryan; Ouédraogo, Jean-Bosco; Rosenthal, Philip J.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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76.756743%
Artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DP), and amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) offer excellent antimalarial efficacy but may select for parasite polymorphisms that decrease drug sensitivity. We evaluated the selection of known polymorphisms in genes encoding putative transporters (pfcrt and pfmdr1) and SP targets (pfdhfr and pfdhps) in parasites that caused new infections within 42 days of therapy for uncomplicated falciparum malaria in Burkina Faso. In 559 children in 2006, 42-day genotype-uncorrected failures were seen in 31.2% with AL, 11.8% with AQ-SP, and 7.6% with DP. After prior AL therapy, selection of wild-type sequences was seen for K76T in pfcrt (72.7% mixed or mutant results pretreatment versus 52.1% in new infections; P = 0.008) and N86Y (36.0% versus 18.7%; P = 0.025) and Y184F (66.7% versus 45.8%; P = 0.009) in pfmdr1. After prior AQ-SP therapy, selection of mutant sequences was seen for N51I (30.8% versus 61.5%; P = 0.05), C59R (28.2% versus 76.9%; P = 0.002), and S108N (30.8% versus 76.9%; P = 0.005) in pfdhfr. After prior DP therapy, selection was not seen for K76T (72.7% versus 77.8%; P = 0.96) in pfcrt or N86Y (36.0% versus 33.3%; P = 0.84), Y184F (66.7% versus 77.8%; P = 0.39)...

Emergence of Resistance among USA300 Methicillin-Resistant Staphylococcus aureus Isolates Causing Invasive Disease in the United States▿

McDougal, Linda K.; Fosheim, Gregory E.; Nicholson, Ainsley; Bulens, Sandra N.; Limbago, Brandi M.; Shearer, Julia E. S.; Summers, Anne O.; Patel, Jean B.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates are usually resistant only to oxacillin, erythromycin, and, increasingly, levofloxacin. Of these, oxacillin and levofloxacin resistances are chromosomally encoded. Plasmid-mediated clindamycin, mupirocin, and/or tetracycline resistance has been observed among USA300 isolates, but these descriptions were limited to specific patient populations or isolated occurrences. We examined the antimicrobial susceptibilities of invasive MRSA isolates from a national surveillance population in order to identify USA300 isolates with unusual, possibly emerging, plasmid-mediated antimicrobial resistance. DNA from these isolates was assayed for the presence of resistance determinants and the presence of a pSK41-like conjugative plasmid. Of 823 USA300 isolates, 72 (9%) were tetracycline resistant; 69 of these were doxycycline susceptible and tetK positive, and 3 were doxycycline resistant and tetM positive. Fifty-one (6.2%) isolates were clindamycin resistant and ermC positive; 22 (2.7%) isolates were high-level mupirocin resistant (mupA positive); 5 (0.6%) isolates were trimethoprim-sulfamethoxazole (TMP-SMZ) resistant, of which 4 were dfrA positive; and 7 (0.9%) isolates were gentamicin resistant and aac6′-aph2″ positive. Isolates with pSK41-like plasmids (n = 24) were positive for mupA (n = 19)...

SREBP-Dependent Triazole Susceptibility in Aspergillus fumigatus Is Mediated through Direct Transcriptional Regulation of erg11A (cyp51A)

Blosser, Sara J.; Cramer, Robert A.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2012 Português
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As triazole antifungal drug resistance during invasive Aspergillus fumigatus infection has become more prevalent, the need to understand mechanisms of resistance in A. fumigatus has increased. The presence of two erg11 (cyp51) genes in Aspergillus spp. is hypothesized to account for the inherent resistance of this mold to the triazole fluconazole (FLC). Recently, an A. fumigatus null mutant of a transcriptional regulator in the sterol regulatory element binding protein (SREBP) family, the ΔsrbA strain, was found to have increased susceptibility to FLC and voriconazole (VCZ). In this study, we examined the mechanism engendering the observed increase in A. fumigatus triazole susceptibility in the absence of SrbA. We observed a significant reduction in the erg11A transcript in the ΔsrbA strain in response to FLC and VCZ. Transcript levels of erg11B were also reduced but not to the extent of erg11A. Interestingly, erg11A transcript levels increased upon extended VCZ, but not FLC, exposure. Construction of an erg11A conditional expression strain in the ΔsrbA strain was able to restore erg11A transcript levels and, consequently, wild-type MICs to the triazole FLC. The VCZ MIC was also partially restored upon increased erg11A transcript levels; however...

Mechanisms of Resistance to Chloramphenicol in Pseudomonas putida KT2440

Fernández, Matilde; Conde, Susana; de la Torre, Jesús; Molina-Santiago, Carlos; Ramos, Juan-Luis; Duque, Estrella
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/2012 Português
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76.837%
Pseudomonas putida KT2440 is a chloramphenicol-resistant bacterium that is able to grow in the presence of this antibiotic at a concentration of up to 25 μg/ml. Transcriptomic analyses revealed that the expression profile of 102 genes changed in response to this concentration of chloramphenicol in the culture medium. The genes that showed altered expression include those involved in general metabolism, cellular stress response, gene regulation, efflux pump transporters, and protein biosynthesis. Analysis of a genome-wide collection of mutants showed that survival of a knockout mutant in the TtgABC resistance-nodulation-division (RND) efflux pump and mutants in the biosynthesis of pyrroloquinoline (PQQ) were compromised in the presence of chloramphenicol. The analysis also revealed that an ABC extrusion system (PP2669/PP2668/PP2667) and the AgmR regulator (PP2665) were needed for full resistance toward chloramphenicol. Transcriptional arrays revealed that AgmR controls the expression of the pqq genes and the operon encoding the ABC extrusion pump from the promoter upstream of open reading frame (ORF) PP2669.

Real-Time Sequencing To Decipher the Molecular Mechanism of Resistance of a Clinical Pan-Drug-Resistant Acinetobacter baumannii Isolate from Marseille, France

Rolain, Jean-Marc; Diene, Seydina M.; Kempf, Marie; Gimenez, Gregory; Robert, Catherine; Raoult, Didier
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /01/2013 Português
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76.82206%
We compare the whole-genome sequences of two multidrug-resistant clinical Acinetobacter baumannii isolates recovered in the same patient before (ABIsac_ColiS susceptible to colistin and rifampin only) and after (ABIsac_ColiR resistant to colistin and rifampin) treatment with colistin and rifampin. We decipher all the molecular mechanisms of antibiotic resistance, and we found mutations in the rpoB gene and in the PmrAB two-component system explaining resistance to rifampin and colistin in ABIsac_ColiR, respectively.

Redefining the Role of the β-Lactamase Locus in Methicillin-Resistant Staphylococcus aureus: β-Lactamase Regulators Disrupt the MecI-Mediated Strong Repression on mecA and Optimize the Phenotypic Expression of Resistance in Strains with Constitutive mecA Expression

Arêde, Pedro; Ministro, Joana; Oliveira, Duarte C.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2013 Português
Relevância na Pesquisa
76.792095%
In response to β-lactam chemotherapy, Staphylococcus aureus has acquired two resistance determinants: blaZ, coding for β-lactamase, which confers resistance to penicillins only, and mecA, coding for an extra cell wall cross-linking enzyme with reduced affinity for virtually all other β-lactams. The transcriptional control of both resistance determinants is regulated by homologous repressors (BlaI and MecI, respectively) and sensor inducers (BlaR1 and MecR1, respectively). There is a cross-talk between the two regulatory systems, and it has been demonstrated that bla regulators stabilize the mecA acquisition. In a recent study, we have unexpectedly observed that in most MRSA strains, there was no significant change in the resistance phenotype upon the overexpression in trans of a MecI repressor, whereas in those few strains negative for the bla locus, there was a massive decrease of resistance (D. C. Oliveira and H. de Lencastre, PLoS One 6:e23287, 2011). Here, we demonstrate that, contrary to what is currently accepted, the bla regulatory system efficiently disrupts the strong MecI-mediated repression on mecA, enabling the optimal expression of resistance. This effect appears to be due to the formation of MecI::BlaI heterodimers that might bind less efficiently to the mecA promoter and become nonfunctional due to the proteolytic inactivation of the BlaI monomer. In addition...

Correlation between Plasmodium yoelii nigeriensis Susceptibility to Artemisinin and Alkylation of Heme by the Drug

Robert, Anne; Claparols, Catherine; Witkowski, Benoit; Benoit-Vical, Françoise
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/2013 Português
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76.76434%
Evidence of artemisinin (ART) resistance in all of the Greater Mekong Region is currently of major concern. Understanding of the mechanisms of resistance developed by Plasmodium against artemisinin and its derivatives is urgently needed. We here demonstrated that ART was able to alkylate heme in mice infected by the ART-susceptible strain of Plasmodium yoelii nigeriensis, Y-control. After long-term drug pressure, the parasite strain (Y-ART3) was 5-fold less susceptible to ART than Y-control. In the blood of mice infected by Y-ART3, no heme-artemisinin adducts could be detected. After release of ART drug pressure, the parasite strain obtained (Y-REL) regained both drug susceptibility to ART and increased ability to produce covalent heme-artemisinin adducts. The correlation between parasite ART susceptibility and alkylation of heme by the drug confirms that heme or hemozoin metabolism is a key target for efficacy of ART as an antimalarial.

Genetic Basis of Resistance to Fusidic Acid in Staphylococci▿

O'Neill, A. J.; McLaws, F.; Kahlmeter, G.; Henriksen, A. S.; Chopra, I.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
Português
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Resistance to fusidic acid in Staphylococcus aureus often results from acquisition of the fusB determinant or from mutations in the gene (fusA) that encodes the drug target (elongation factor G). We now report further studies on the genetic basis of resistance to this antibiotic in the staphylococci. Two staphylococcal genes that encode proteins exhibiting ca. 45% identity with FusB conferred resistance to fusidic acid in S. aureus. One of these genes (designated fusC) was subsequently detected in all fusidic acid-resistant clinical strains of S. aureus tested that did not carry fusB or mutations in fusA, and in strains of S. intermedius. The other gene (designated fusD) is carried by S. saprophyticus, explaining the inherent resistance of this species to fusidic acid. Fusidic acid-resistant strains of S. lugdunensis harbored fusB. Thus, resistance to fusidic acid in clinical isolates of S. aureus and other staphylococcal species frequently results from expression of FusB-type proteins.