scholarly journals Loss of GdpP function in Staphylococcus aureus leads to β-lactam tolerance and enhanced evolution of β-lactam resistance

2021 ◽  
Author(s):  
Raymond Poon ◽  
Li Basuino ◽  
Nidhi Satishkumar ◽  
Aditi Chatterjee ◽  
Nagaraja Mukkayyan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Second Messenger ◽  
Drug Tolerance ◽  
Selective Advantage ◽  
Therapy Failure ◽  
Bacterial Colony ◽  
Colony Forming Units ◽  
Resistance Loss ◽  
High Level

Infections caused by Staphylococcus aureus are a leading cause of mortality. Treating infections caused by S. aureus is difficult due to resistance against most traditional antibiotics, including β-lactams. We previously reported the presence of mutations in gdpP among S. aureus strains that were obtained by serial passaging in β-lactam drugs. Similar mutations have recently been reported in natural S. aureus isolates that are either non-susceptible or resistant to β-lactam antibiotics. gdpP codes for a phosphodiesterase that cleaves cyclic-di-AMP (CDA), a newly discovered second messenger. In this study, we sought to identify the role of gdpP in β-lactam resistance in S. aureus . Our results showed that gdpP associated mutations caused loss of phosphodiesterase function, leading to increased CDA accumulation in the bacterial cytosol. Deletion of gdpP led to an enhanced ability of the bacteria to withstand a β-lactam challenge (two to three log increase in bacterial colony forming units) by promoting tolerance without enhancing MICs of β-lactam antibiotics. Our results demonstrated that increased drug tolerance due to loss of GdpP function can provide a selective advantage in acquisition of high-level β-lactam resistance. Loss of GdpP function thus increases tolerance to β-lactams that can lead to its therapy failure and can permit β-lactam resistance to occur more readily.

scholarly journals Loss of GdpP function in Staphylococcus aureus leads to β-lactam tolerance and enhanced evolution of β-lactam resistance

2021 ◽  
Author(s):  
Raymond Poon ◽  
Li Basuino ◽  
Nidhi Satishkumar ◽  
Aditi Chatterjee ◽  
Nagaraja Mukkayyan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Selective Advantage ◽  
Mass Spectrometric ◽  
Spectrometric Analysis ◽  
Therapy Failure ◽  
Bacterial Colony ◽  
Deletion Mutagenesis ◽  
Colony Forming Units ◽  
High Level

Background: We previously reported the presence of mutations in gdpP among Staphylococcus aureus strains that were obtained by serial passaging in β-lactam drugs. gdpP codes for a phosphodiesterase that cleaves cyclic-di-AMP (CDA), a newly discovered second messenger. Objectives: We sought to identify the role of gdpP in β-lactam resistance of S. aureus. Methods: CDA concentrations in bacterial cytosol were measured through mass-spectrometric analysis. gdpP deletion mutagenesis and their complemented strains were created in clinically relevant S. aureus strains to characterize its function. Results: gdpP associated mutations among passaged strains were identified to cause loss of phosphodiesterase function, leading to increased CDA accumulation in the bacterial cytosol. Deletion of gdpP led to an enhanced ability of the bacteria to withstand a β-lactam challenge (two to three log increase in bacterial colony forming units) by promoting tolerance without enhancing MICs of β-lactam antibiotics. Our results demonstrate that increased drug tolerance due to loss of GdpP function can provide a selective advantage in acquisition of high-level β-lactam resistance and could lead to β-lactam treatment failure of S. aureus infections. Conclusions: Loss of GdpP function increases tolerance to β-lactams that can lead to its therapy failure and can permit β-lactam resistance to occur more readily.

Large-Scale Screening and Identification of Novel Pathogenic Staphylococcus aureus Genes Using a Silkworm Infection Model

2020 ◽  
Vol 221 (11) ◽  
pp. 1795-1804 ◽  
Author(s):  
Atmika Paudel ◽  
Hiroshi Hamamoto ◽  
Suresh Panthee ◽  
Yasuhiko Matsumoto ◽  
Kazuhisa Sekimizu
Keyword(s):  
Staphylococcus Aureus ◽  
Large Scale ◽  
Opportunistic Pathogen ◽  
Infection Model ◽  
Colony Forming Units ◽  
Screening And Identification ◽  
Transposon Mutants ◽  
Pathogenicity Tests ◽  
Large Scale Screening

Abstract The regulatory network of virulence factors produced by the opportunistic pathogen Staphylococcus aureus is unclear and the functions of many uncharacterized genes in its genome remain to be elucidated. In this study, we screened 380 genes whose function was unassigned, utilizing gene-disrupted transposon mutants of the community-acquired methicillin-resistant S. aureus USA300 for pathogenicity in silkworms. We identified 10 strains with reduced silkworm killing ability. Among them, 8 displayed reduced virulence in a mouse model as evidenced by reduced colony-forming units in organs of infected mice. The role of each gene in pathogenicity was further confirmed by complementation and pathogenicity tests in silkworms, where we found that the phenotype was not restored in 1 strain. Additionally, some of the mutants displayed reduced hemolysis, proteolysis, pigment production, and survival in murine RAW 264.7 monocyte-macrophage cells. These newly identified genes involved in virulence will enhance our understanding of the pathogenicity of S. aureus.

scholarly journals Ceftobiprole- and Ceftaroline-Resistant Methicillin-Resistant Staphylococcus aureus

2015 ◽  
Vol 59 (5) ◽  
pp. 2960-2963 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Binh Diep ◽  
Stephanie Hamilton ◽  
Som S. Chatterjee ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
Low Level ◽  
Mrsa Strains ◽  
High Level ◽  
Level Resistance

ABSTRACTThe role ofmecAmutations in conferring resistance to ceftobiprole and ceftaroline, cephalosporins with anti-methicillin-resistantStaphylococcus aureus(MRSA) activity, was determined with MRSA strains COL and SF8300. The SF8300 ceftaroline-passaged mutant carried a singlemecAmutation, E447K (E-to-K change at position 447), and expressed low-level resistance. This mutation in COL conferred high-level resistance to ceftobiprole but only low-level resistance to ceftaroline. The COL ceftaroline-passaged mutant, which expressed high-level resistance to ceftobiprole and ceftaroline, had mutations inpbp2,pbp4, andgdpPbut notmecA.

scholarly journals The Anti-Methicillin-Resistant Staphylococcus aureus Quinolone WCK 771 Has Potent Activity against Sequentially Selected Mutants, Has a Narrow Mutant Selection Window against Quinolone-Resistant Staphylococcus aureus, and Preferentially Targets DNA Gyrase

2006 ◽  
Vol 50 (11) ◽  
pp. 3568-3579 ◽  
Author(s):  
Sachin S. Bhagwat ◽  
Lakshmi A. Mundkur ◽  
Shrikant V. Gupte ◽  
Mahesh V. Patel ◽  
Habil F. Khorakiwala
Keyword(s):  
Staphylococcus Aureus ◽  
Dna Gyrase ◽  
Primary Target ◽  
Topoisomerase Iv ◽  
Mutant Selection ◽  
Low Concentrations ◽  
Selection Window ◽  
High Level ◽  
The Impact

ABSTRACT WCK 771 is a broad-spectrum fluoroquinolone with enhanced activity against quinolone-resistant staphylococci. To understand the impact of the target-level interactions of WCK 771 on its antistaphylococcal pharmacodynamic properties, we determined the MICs for genetically defined mutants and studied the mutant prevention concentrations (MPCs), the frequency of mutation, and the cidality against the wild type and double mutants. There was a twofold increase in the MICs of WCK 771 for single gyrA mutants, indicating that DNA gyrase is its primary target. All first- and second-step mutants selected by WCK 771 revealed gyrA and grlA mutations, respectively. The MICs of WCK 771 and clinafloxacin were found to be superior to those of other quinolones against strains with double and triple mutations. WCK 771 was also cidal for high-density double mutants at low concentrations. WCK 771 and clinafloxacin showed narrow mutant selection windows compared to those of the other quinolones. Against a panel of 50 high-level quinolone-resistant clinical isolates of staphylococci (ciprofloxacin MIC ≥ 16 μg/ml), the WCK 771 MPCs were ≤2 μg/ml for 68% of the strains and ≤4 μg/ml for 28% of the strains. Our results demonstrate that gyrA is the primary target of WCK 771 and that it has pharmacodynamic properties remarkably different from those of quinolones with dual targets (garenoxacin and moxifloxacin) and topoisomerase IV-specific quinolones (trovafloxacin). WCK 771 displayed an activity profile comparable to that of clinafloxacin, a dual-acting quinolone with a high affinity to DNA gyrase. Overall, the findings signify the key role of DNA gyrase in determining the optimal antistaphylococcal features of quinolones.

Searching for ‘success’: generation, gender and onward migration in the Iranian diaspora

2017 ◽  
Vol 14 (1) ◽  
pp. 101-112 ◽  
Author(s):  
Melissa Kelly
Keyword(s):  
Life History ◽  
Young Age ◽  
Onward Migration ◽  
Social Fields ◽  
Transnational Social Fields ◽  
High Level ◽  
Iranian Diaspora

This article uses the concepts of ‘transnational social fields’ and ‘habitus’ to explore the multifaceted role families play in shaping the aspirations of onward migrating youth. The article draws on biographical life history interviews conducted with the children of Iranian migrants who were raised in Sweden but moved to London, UK as adults. The findings of the study suggest that from a young age, all the participants were pressured by their parents to perform well academically, and to achieve high level careers. These goals were easier to achieve in London than in Sweden for several reasons. Interestingly, however, participants’ understandings of what constituted success and their motivations for onward migration were nuanced and varied considerably by gender. The study contributes to an understanding of the role of multi-sited transnational social fields in shaping the aspirations of migrant youths, as well as the strategies taken up by these migrants to achieve their goals.

Decision making power of college girls in relation to clothing

2018 ◽  
Vol 9 (01) ◽  
Author(s):  
Parul Gill ◽  
Poonam Malik ◽  
Pankaj Gill
Keyword(s):  
Decision Making ◽  
Satisfaction Level ◽  
College Going ◽  
Level Of Satisfaction ◽  
High Level ◽  
Garment Design ◽  
Structured Questionnaire

The present study was undertaken to explore the decision making patterns of college girls in relation to clothing and their satisfaction level with these decision making patterns. Thirty under graduate college girls from Panipat city were approached to record their responses regarding decision making in relation to clothing and satisfaction level through a well structured questionnaire. It was found that most of the girls (56.66%) themselves made the decisions about the type of garment (Indian, western or both) they wear and majority of girls (70%) were highly satisfied with this decision making. Parents performed the role of buyers for their college going daughters' garments in most of the cases (63.33%) and the 73.33% girls had high level of satisfaction with this. In most of the cases (60%) the decision about the garment design was made by the girls themselves and they were highly satisfied with it. Keywords: clothing, college, girls, decision making.

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