scholarly journals Transcriptional Repressor PtvR Regulates Phenotypic Tolerance to Vancomycin in Streptococcus pneumoniae

2017 ◽  
Vol 199 (14) ◽  
Author(s):  
Xue Liu ◽  
Jing-Wen Li ◽  
Zhixing Feng ◽  
Youfu Luo ◽  
Jan-Willem Veening ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Treatment Failure ◽  
Molecular Mechanisms ◽  
Transcriptional Repressor ◽  
Drug Tolerance ◽  
Microbial Populations ◽  
Luciferase Reporter ◽  
Chronic Infections ◽  
Mobility Shift ◽  
Content Type

ABSTRACT Reversible or phenotypic tolerance to antibiotics within microbial populations has been implicated in treatment failure of chronic infections and development of persister cells. However, the molecular mechanisms regulating phenotypic drug tolerance are largely unknown. In this study, we identified a four-gene operon in Streptococcus pneumoniae that contributes to phenotypic tolerance to vancomycin (ptv). RNA sequencing, quantiative reverse transcriptase PCR, and transcriptional luciferase reporter experiments revealed that transcription of the ptv operon (consisting of ptvR, ptvA, ptvB, and ptvC) is induced by exposure to vancomycin. Further investigation showed that transcription of the ptv operon is repressed by PtvR, a PadR family repressor. Transcriptional induction of the ptv operon by vancomycin was achieved by transcriptional derepression of this locus, which was mediated by PtvR. Importantly, fully derepressing ptvABC by deleting ptvR or overexpressing the ptv operon with an exogenous promoter significantly enhanced vancomycin tolerance. Gene deletion analysis revealed that PtvA, PtvB, and PtvC are all required for the PtvR-regulated phenotypic tolerance to vancomycin. Finally, the results of an electrophoretic mobility shift assay with recombinant PtvR showed that PtvR represses the transcription of the ptv operon by binding to two palindromic sequences within the ptv promoter. Together, the ptv locus represents an inducible system in S. pneumoniae in response to stressful conditions, including those caused by antibiotics. IMPORTANCE Reversible or phenotypic tolerance to antibiotics within microbial populations is associated with treatment failure of bacterial diseases, but the underlying mechanisms regulating phenotypic drug tolerance remain obscure. This study reports our finding of a multigene locus that contributes to inducible tolerance to vancomycin in Streptococcus pneumoniae, an important opportunistic human pathogen. The vancomycin tolerance phenotype depends on the PtvR transcriptional repressor and three predicted membrane-associated proteins encoded by the ptv locus. This represents the first example of a gene locus in S. pneumoniae that is responsible for antibiotic tolerance and has important implications for further understanding bacterial responses and phenotypic tolerance to antibiotic treatment in this and other pathogens.

scholarly journals Fis Contributes to Resistance of Pseudomonas aeruginosa to Ciprofloxacin by Regulating Pyocin Synthesis

2020 ◽  
Vol 202 (11) ◽  
Author(s):  
Yuqing Long ◽  
Weixin Fu ◽  
Su Wang ◽  
Xuan Deng ◽  
Yongxin Jin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Bacterial Resistance ◽  
Global Gene Expression ◽  
Chronic Infections ◽  
Mobility Shift ◽  
Content Type ◽  
Regulatory Pathways ◽  
Opportunistic Pathogenic

ABSTRACT Factor for inversion stimulation (Fis) is a versatile DNA binding protein that plays an important role in coordinating bacterial global gene expression in response to growth phases and environmental stresses. Previously, we demonstrated that Fis regulates the type III secretion system (T3SS) in Pseudomonas aeruginosa. In this study, we explored the role of Fis in the antibiotic resistance of P. aeruginosa and found that mutation of the fis gene increases the bacterial susceptibility to ciprofloxacin. We further demonstrated that genes related to pyocin biosynthesis are upregulated in the fis mutant. The pyocins are produced in response to genotoxic agents, including ciprofloxacin, and the release of pyocins results in lysis of the producer cell. Thus, pyocin biosynthesis genes sensitize P. aeruginosa to ciprofloxacin. We found that PrtN, the positive regulator of the pyocin biosynthesis genes, is upregulated in the fis mutant. Genetic experiments and electrophoretic mobility shift assays revealed that Fis directly binds to the promoter region of prtN and represses its expression. Therefore, our results revealed novel Fis-mediated regulation on pyocin production and bacterial resistance to ciprofloxacin in P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is an important opportunistic pathogenic bacterium that causes various acute and chronic infections in human, especially in patients with compromised immunity, cystic fibrosis (CF), and/or severe burn wounds. About 60% of cystic fibrosis patients have a chronic respiratory infection caused by P. aeruginosa. The bacterium is intrinsically highly resistant to antibiotics, which greatly increases difficulties in clinical treatment. Therefore, it is critical to understand the mechanisms and the regulatory pathways that are involved in antibiotic resistance. In this study, we elucidated a novel regulatory pathway that controls the bacterial resistance to fluoroquinolone antibiotics, which enhances our understanding of how P. aeruginosa responds to ciprofloxacin.

scholarly journals PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin

2014 ◽  
Vol 82 (4) ◽  
pp. 1638-1647 ◽  
Author(s):  
Ziyu Sun ◽  
Jing Shi ◽  
Chang Liu ◽  
Yongxin Jin ◽  
Kewei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pseudomonas Aeruginosa ◽  
Bacterial Colonization ◽  
Mrna Level ◽  
Sos Response ◽  
Opportunistic Pathogen ◽  
Host Cells ◽  
Chronic Infections ◽  
Mobility Shift ◽  
Content Type

ABSTRACTPseudomonas aeruginosais an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced byP. aeruginosathat are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR, which gets cleaved under SOS response, leading to upregulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component ofP. aeruginosa. In this study, we demonstrate that mutation inprtRresults in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce the SOS response and pyocin production, resulted in an elevated PrtR mRNA level. Overexpression of PrtR by atacpromoter repressed the endogenousprtRpromoter activity, and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. A high level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of a relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production.

scholarly journals MiR-4310 Induced by SP1 targets PTEN to Promote Glioma Progression

2020 ◽  
Author(s):  
Wu Zhiyong ◽  
Luo Jie ◽  
Huang Tengyue ◽  
Yi Renhui ◽  
Ding Shengfeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
Glioma Progression

Abstract Background: miRNAs have been reported to be involved in multiple biological processes of gliomas. Here, we aimed to analyze miR-4310 and its correlation genes involved in the tumor progression of human glioma.Methods: miR-4310 expression levels were examined in glioma and non-tumor brain (NB) tissues. The molecular mechanisms of miR-4310 expression and its effects on cell proliferation, migration, and invasion were explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) , Transwell chamber, Boyden chamber, and western blot analyses, as well as in vivo tumorigenesis in nude mice. The relationships among miR-4310, SP1, and phosphatase and tensin homolog (PTEN) were explored by chromatin immunoprecipitation (ChIP), agarose gel electrophoresis, electrophoresis mobility shift (EMSA), and dual luciferase reporter gene assays. Results: miR-4310 expression was upregulated in glioma tissues compared to NB. Overexpressed miR-4310 promoted glioma cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo . Inhibition of miR-4310 was sufficient to reverse these results. Mechanistic analyses revealed that miR-4310 promoted glioma progression through the PI3K/AKT pathway by targeting PTEN. Additionally, SP1 induced the expression of miR-4310 by binding to its promoter region. Conclusion: miR-4310 promotes the progression of glioma by targeting PTEN and activating the PI3K/AKT pathway meanwhile the expression of miR-4310 is induced by SP1.

scholarly journals Redox-Regulated Adaptation of Streptococcus oligofermentans to Hydrogen Peroxide Stress

mSystems ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Huichun Tong ◽  
Yuzhu Dong ◽  
Xinhui Wang ◽  
Qingqing Hu ◽  
Fan Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mass Spectrometry ◽  
Inductively Coupled Plasma ◽  
Molecular Mechanisms ◽  
Cysteine Oxidation ◽  
Mobility Shift ◽  
Adaptation Mechanism ◽  
Content Type ◽  
Oxidized Proteins ◽  
Thioredoxin System

ABSTRACT Preexposure to a low concentration of H2O2 significantly increases the survivability of catalase-negative streptococci in the presence of a higher concentration of H2O2. However, the mechanisms of this adaptation remain unknown. Here, using a redox proteomics assay, we identified 57 and 35 cysteine-oxidized proteins in Streptococcus oligofermentans bacteria that were anaerobically cultured and then pulsed with 40 μM H2O2 and that were statically grown in a 40-ml culture, respectively. The oxidized proteins included the peroxide-responsive repressor PerR, the manganese uptake repressor MntR, thioredoxin system proteins Trx and Tpx, and most glycolytic proteins. Cysteine oxidations of these proteins were verified through redox Western blotting, immunoprecipitation, and liquid chromatography-tandem mass spectrometry assays. In particular, Zn2+-coordinated Cys139 and Cys142 mutations eliminated the H2O2 oxidation of PerR, and inductively coupled plasma mass spectrometry detected significantly decreased amounts of Zn2+ in H2O2-treated PerR, demonstrating that cysteine oxidation results in Zn2+ loss. An electrophoretic mobility shift assay (EMSA) determined that the DNA binding of Mn2+-bound PerR protein (PerR:Zn,Mn) was abolished by H2O2 treatment but was restored by dithiothreitol reduction, verifying that H2O2 inactivates streptococcal PerR:Zn,Mn through cysteine oxidation, analogous to the findings for MntR. Quantitative PCR and EMSA demonstrated that tpx, mntA, mntR, and dpr belonged to the PerR regulons but that only dpr was directly regulated by PerR; mntA was also controlled by MntR. Deletion of mntR significantly reduced the low-H2O2-concentration-induced adaptation of S. oligofermentans to a higher H2O2 concentration, while the absence of PerR completely abolished the self-protection. Therefore, a low H2O2 concentration resulted in the cysteine-reversible oxidations of PerR and MntR to derepress their regulons, which function in cellular metal and redox homeostasis and which endow streptococci with the antioxidative capability. This work reveals a novel Cys redox-based H2O2 defense strategy employed by catalase-negative streptococci in Mn2+-rich cellular environments. IMPORTANCE The catalase-negative streptococci produce as well as tolerate high levels of H2O2. This work reports the molecular mechanisms of low-H2O2-concentration-induced adaptation to higher H2O2 stress in a Streptococcus species, in which the peroxide-responsive repressor PerR and its redox regulons play the major role. Distinct from the Bacillus subtilis PerR, which is inactivated by H2O2 through histidine oxidation by the Fe2+-triggered Fenton reaction, the streptococcal PerR is inactivated by H2O2 oxidation of the structural Zn2+ binding cysteine residues and thus derepresses the expression of genes defending against oxidative stress. The reversible cysteine oxidation could provide flexibility for PerR regulation in streptococci, and the mechanism might be widely used by lactic acid bacteria, including pathogenic streptococci, containing high levels of cellular manganese, in coping with oxidative stress. The adaptation mechanism could also be applied in oral hygiene by facilitating the fitness and adaptability of the oral commensal streptococci to suppress the pathogens.

scholarly journals MiR-4310 induced by SP1 targets PTEN to promote glioma progression

2020 ◽  
Author(s):  
Wu Zhiyong ◽  
Luo Jie ◽  
Huang Tengyue ◽  
Yi Renhui ◽  
Ding Shengfeng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Migration And Invasion ◽  
Boyden Chamber ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
Glioma Progression

Abstract Background: miRNAs have been reported to be involved in multiple biological processes of gliomas. Here, we aimed to analyze miR-4310 and its correlation genes involved in the tumor progression of human glioma. Methods: miR-4310 expression levels were examined in glioma and non-tumor brain (NB) tissues. The molecular mechanisms of miR-4310 expression and its effects on cell proliferation, migration, and invasion were explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) , Transwell chamber, Boyden chamber, and western blot analyses, as well as in vivo tumorigenesis in nude mice. The relationships among miR-4310, SP1, and phosphatase and tensin homolog (PTEN) were explored by chromatin immunoprecipitation (ChIP), agarose gel electrophoresis, electrophoresis mobility shift (EMSA), and dual luciferase reporter gene assays. Results: miR-4310 expression was upregulated in glioma tissues compared to NB. Overexpressed miR-4310 promoted glioma cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo . Inhibition of miR-4310 was sufficient to reverse these results. Mechanistic analyses revealed that miR-4310 promoted glioma progression through the PI3K/AKT pathway by targeting PTEN. Additionally, SP1 induced the expression of miR-4310 by binding to its promoter region. Conclusion: miR-4310 promotes the progression of glioma by targeting PTEN and activating the PI3K/AKT pathway meanwhile the expression of miR-4310 is induced by SP1.

scholarly journals The ParB-parS Chromosome Segregation System Modulates Competence Development in Streptococcus pneumoniae

mBio ◽  
2015 ◽  
Vol 6 (4) ◽  
Author(s):  
Laetitia Attaiech ◽  
Anita Minnen ◽  
Morten Kjos ◽  
Stephan Gruber ◽  
Jan-Willem Veening
Keyword(s):  
Streptococcus Pneumoniae ◽  
Chromosome Segregation ◽  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Competence Development ◽  
Human Pathogen ◽  
Transcription Analysis ◽  
Exogenous Dna ◽  
Content Type

ABSTRACT ParB proteins bind centromere-like DNA sequences called parS sites and are involved in plasmid and chromosome segregation in bacteria. We previously showed that the opportunistic human pathogen Streptococcus pneumoniae contains four parS sequences located close to the origin of replication which are bound by ParB. Using chromatin immunoprecipitation (ChIP), we found here that ParB spreads out from one of these parS sites, parS(−1.6°), for more than 5 kb and occupies the nearby comCDE operon, which drives competence development. Competence allows S. pneumoniae to take up DNA from its environment, thereby mediating horizontal gene transfer, and is also employed as a general stress response. Mutating parS(−1.6°) or deleting parB resulted in transcriptional up-regulation of comCDE and ssbB (a gene belonging to the competence regulon), demonstrating that ParB acts as a repressor of competence. However, genome-wide transcription analysis showed that ParB is not a global transcriptional regulator. Different factors, such as the composition of the growth medium and antibiotic-induced stress, can trigger the sensitive switch driving competence. This work shows that the ParB-parS chromosome segregation machinery also influences this developmental process. IMPORTANCE Streptococcus pneumoniae (pneumococcus) is an important human pathogen responsible for more than a million deaths each year. Like all other organisms, S. pneumoniae must be able to segregate its chromosomes properly. Not only is understanding the molecular mechanisms underlying chromosome segregation in S. pneumoniae therefore of fundamental importance, but also, this knowledge might offer new leads for ways to target this pathogen. Here, we identified a link between the pneumococcal chromosome segregation system and the competence-developmental system. Competence allows S. pneumoniae to take up and integrate exogenous DNA in its chromosome. This process plays a crucial role in successful adaptation to—and escape from—host defenses, antibiotic treatments, and vaccination strategies. We show that the chromosome segregation protein ParB acts as a repressor of competence. To the best of our knowledge, this is the first example of a ParB protein controlling bacterial competence.

scholarly journals Recycling of Peptidyl-tRNAs by Peptidyl-tRNA Hydrolase Counteracts Azithromycin-Mediated Effects on Pseudomonas aeruginosa

2013 ◽  
Vol 57 (4) ◽  
pp. 1617-1624 ◽  
Author(s):  
Julia Gödeke ◽  
Christian Pustelny ◽  
Susanne Häussler
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Opportunistic Pathogen ◽  
Phase Cell ◽  
Chronic Infections ◽  
Content Type ◽  
Mediated Effects ◽  
Protein Expression Profiles ◽  
The Impact

ABSTRACTAcute and chronic infections caused by the opportunistic pathogenPseudomonas aeruginosapose a serious threat to human health worldwide, and its increasing resistance to antibiotics requires alternative treatments that are more effective than available strategies. Clinical studies have clearly demonstrated that cystic fibrosis (CF) patients with chronicP. aeruginosainfections benefit from long-term low-dose azithromycin (AZM) treatment. Immunomodulating activity, the impact of AZM on the expression of quorum-sensing-dependent virulence factors, type three secretion, and motility inP. aeruginosaseem to contribute to the therapeutic response. However, to date, the molecular mechanisms underlying these AZM effects have remained elusive. Our data indicate that the AZM-mediated phenotype is caused by a depletion of the intracellular pools of tRNAs available for protein synthesis. Overexpression of theP. aeruginosapeptidyl-tRNA hydrolase, which recycles the tRNA from peptidyl-tRNA drop-off during translation, counteracted the effects of AZM on stationary-phase cell killing, cytotoxicity, and the production of rhamnolipids and partially restored swarming motility. Intriguingly, the exchange of a rare for a frequent codon inrhlRalso explicitly diminished the AZM-mediated decreased production of rhamnolipids. These results indicate that depletion of the tRNA pools by AZM seems to affect the translation of genes that use rare aminoacyl-tRNA isoacceptors to a great extent and might explain the selective activity of AZM on theP. aeruginosaproteome and possibly also on the protein expression profiles of other bacterial pathogens.

scholarly journals Evolution of Antibiotic Tolerance Shapes Resistance Development in Chronic Pseudomonas aeruginosa Infections

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Isabella Santi ◽  
Pablo Manfredi ◽  
Enea Maffei ◽  
Adrian Egli ◽  
Urs Jenal
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Prolonged Exposure ◽  
Drug Tolerance ◽  
Antibiotic Tolerance ◽  
Human Pathogen ◽  
Chronic Infections ◽  
Resistance Development ◽  
Content Type

ABSTRACT The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed the inpatient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro, and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multidrug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections. IMPORTANCE Over the past decades, pan-resistant strains of major bacterial pathogens have emerged and have rendered clinically available antibiotics ineffective, putting at risk many of the major achievements of modern medicine, including surgery, cancer therapy, and organ transplantation. A thorough understanding of processes leading to the development of antibiotic resistance in human patients is thus urgently needed. We show that drug tolerance, the ability of bacteria to survive prolonged exposure to bactericidal antibiotics, rapidly evolves in the opportunistic human pathogen Pseudomonas aeruginosa upon recurrent exposures to antibiotics. Our studies show that tolerance protects P. aeruginosa against different classes of antibiotics and that it generally precedes and promotes resistance development. The rapid evolution of tolerance during treatment regimens may thus act as a strong driving force to accelerate antibiotic resistance development. To successfully counter resistance, diagnostic measures and novel treatment strategies will need to incorporate the important role of antibiotic tolerance.

scholarly journals Regulation of AmpC-Driven β-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling

mSystems ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Gabriel Torrens ◽  
Sara Belén Hernández ◽  
Juan Alfonso Ayala ◽  
Bartolome Moya ◽  
Carlos Juan ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Molecular Mechanisms ◽  
Resistance Mechanism ◽  
Quantitative Information ◽  
Chronic Infections ◽  
Knockout Mutant ◽  
Major Step ◽  
Content Type ◽  
Soluble Cell

ABSTRACT The hyperproduction of the chromosomal AmpC β-lactamase is the main mechanism driving β-lactam resistance in Pseudomonas aeruginosa, one of the leading opportunistic pathogens causing nosocomial acute and chronic infections in patients with underlying respiratory diseases. In the current scenario of the shortage of effective antipseudomonal drugs, understanding the molecular mechanisms mediating AmpC hyperproduction in order to develop new therapeutics against this fearsome pathogen is of great importance. It has been accepted for decades that certain cell wall-derived soluble fragments (muropeptides) modulate AmpC production by complexing with the transcriptional regulator AmpR and acquiring different conformations that activate/repress ampC expression. However, these peptidoglycan-derived signals have never been characterized in the highly prevalent P. aeruginosa stable AmpC hyperproducer mutants. Here, we demonstrate that the previously described fragments enabling the transient ampC hyperexpression during cefoxitin induction (1,6-anhydro-N-acetylmuramyl-pentapeptides) also underlie the dacB (penicillin binding protein 4 [PBP4]) mutation-driven stable hyperproduction but differ from the 1,6-anhydro-N-acetylmuramyl-tripeptides notably overaccumulated in the ampD knockout mutant. In addition, a simultaneous greater accumulation of both activators appears linked to higher levels of AmpC hyperproduction, although our results suggest a much stronger AmpC-activating potency for the 1,6-anhydro-N-acetylmuramyl-pentapeptide. Collectively, our results propose a model of AmpC control where the activator fragments, with qualitative and quantitative particularities depending on the pathways and levels of β-lactamase production, dominate over the repressor (UDP-N-acetylmuramyl-pentapeptide). This study represents a major step in understanding the foundations of AmpC-dependent β-lactam resistance in P. aeruginosa, potentially useful to open new therapeutic conceptions intended to interfere with the abovementioned cell wall-derived signaling. IMPORTANCE The extensive use of β-lactam antibiotics and the bacterial adaptive capacity have led to the apparently unstoppable increase of antimicrobial resistance, one of the current major global health challenges. In the leading nosocomial pathogen Pseudomonas aeruginosa, the mutation-driven AmpC β-lactamase hyperproduction stands out as the main resistance mechanism, but the molecular cues enabling this system have remained elusive until now. Here, we provide for the first time direct and quantitative information about the soluble cell wall-derived fragments accounting for the different levels and pathways of AmpC hyperproduction. Based on these results, we propose a hierarchical model of signals which ultimately govern ampC hyperexpression and resistance.

scholarly journals Serotype Emergence and Genotype Distribution among Macrolide-Resistant Invasive Streptococcus Pneumoniae Isolates in the Postconjugate Vaccine (PCV-7) Era

2011 ◽  
Vol 56 (2) ◽  
pp. 743-750 ◽  
Author(s):  
Zhenying Liu ◽  
Irving Nachamkin ◽  
Paul H. Edelstein ◽  
Ebbing Lautenbach ◽  
Joshua P. Metlay
Keyword(s):  
Streptococcus Pneumoniae ◽  
Gel Electrophoresis ◽  
Molecular Mechanisms ◽  
Population Based ◽  
Resistance Rate ◽  
Pulsed Field Gel Electrophoresis ◽  
Genotype Distribution ◽  
Erythromycin Resistance ◽  
Content Type ◽  
Pneumococcal Bacteremia

ABSTRACTWe conducted population-based surveillance for pneumococcal bacteremia within a 5-county region surrounding Philadelphia from October 2001 through September 2008, the period following introduction of the seven-valent pneumococcal conjugate vaccine. Erythromycin resistance increased from 14.7% in 2001-2002 to 20.3% in 2007-2008, while the resistance rate to penicillin (MIC, ≥2 μg/ml) decreased from 7.2% to 4.2% during the same period. The most predominant serotypes associated with erythromycin resistance in 2007-2008 included 19A (29.7%), 15A (29.2%), 6C (10.1%), 3 (5.6%), and 6A (4.5%). The molecular mechanisms for the increasing erythromycin resistance were mainly due to the growing presence ofmef(A)negativeerm(B)+andmef(A)+erm(B)+genotypes, which increased from 20.0% to 46.1% and from 1.8% to 19.1%, respectively, from 2001-2002 to 2007-2008. However,mef(A)-mediated erythromycin resistance decreased from 72.7% in 2001-2002 to 34.8% in 2007-2008. Serotypes related to theerm(B) gene were 15A (45.6%), 19A (20.9%), 3 (10.1%), and 6B (6.3%); serotypes related to themef(A)gene were 6A (18.6%), 19A (15.0%), 6C (9.3%), and 14(8.4%); serotypes associated with the presence of botherm(B) andmef(A)were 19A (81.5%), 15A (7.7%), and 19F (6.2%). Pulsed-field gel electrophoresis analysis demonstrated that erythromycin-resistant isolates within the 19A serotype were genetically diverse and related to several circulating international clones. In contrast, erythromycin-resistant isolates within the 15A serotype consisted of clonally identical or closely related isolates.

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