Structure and Function of the Genomically Encoded Fosfomycin Resistance Enzyme, FosB, from <i>Staphylococcus aureus</i>

Thompson, Matthew K.; Keithly, M.E.; Goodman, Michael C.; Hammer, Neal D.; Cook, P.D.; Jagessar, K.; Harp, Joel M.; Skaar, Eric P.; Armstrong, Richard N.

doi:10.1021/bi4015852

Cited by 45 publications

(41 citation statements)

References 43 publications

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“…The S. aureus JE2 strain carries the acquired resistance genes mecA and fosB on the chromosome (Fey et al, 2013), which confer resistance to β-lactams (Zapun et al, 2008) and fosfomycin (Thompson et al, 2014), respectively. As a verification of the screen, we indeed identified the mecA and fosB mutants as more susceptible to oxacillin and fosfomycin, respectively ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

et al. 2016

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The emergence of antimicrobial resistance severely threatens our ability to treat bacterial infections. While acquired resistance has received considerable attention, relatively little is known of intrinsic resistance that allows bacteria to naturally withstand antimicrobials. Gene products that confer intrinsic resistance to antimicrobial agents may be explored for alternative antimicrobial therapies, by potentiating the efficacy of existing antimicrobials. In this study, we identified the intrinsic resistome to a broad spectrum of antimicrobials in the human pathogen, Staphylococcus aureus. We screened the Nebraska Transposon Mutant Library of 1920 single-gene inactivations in S. aureus strain JE2, for increased susceptibility to the anti-staphylococcal antimicrobials (ciprofloxacin, oxacillin, linezolid, fosfomycin, daptomycin, mupirocin, vancomycin, and gentamicin). Sixty-eight mutants were confirmed by E-test to display at least twofold increased susceptibility to one or more antimicrobial agents. The majority of the identified genes have not previously been associated with antimicrobial susceptibility in S. aureus. For example, inactivation of genes encoding for subunits of the ATP synthase, atpA, atpB, atpG and atpH, reduced the minimum inhibitory concentration (MIC) of gentamicin 16-fold. To elucidate the potential of the screen, we examined treatment efficacy in the Galleria mellonella infection model. Gentamicin efficacy was significantly improved, when treating larvae infected with the atpA mutant compared to wild type cells with gentamicin at a clinically relevant concentration. Our results demonstrate that many gene products contribute to the intrinsic antimicrobial resistance of S. aureus. Knowledge of these intrinsic resistance determinants provides alternative targets for compounds that may potentiate the efficacy of existing antimicrobial agents against this important pathogen.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

et al. 2016

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“…The biochemical activity has been demonstrated for various Bacillus and Staphylococcus FosB homologs (Lamers et al, 2012 ; Roberts et al, 2013 ; Thompson et al, 2013 ). In B. subtilis and S. aureus , both FosB and BSH confer resistance to fosfomycin treatment in survival assays in vivo (Gaballa et al, 2010 ; Thompson et al, 2014 ). Co-crystallization of S. aureus FosB with L-Cys or BSH revealed a mixed disulfide at the active site Cys9 of FosB which is unique in FosB from S. aureus (Thompson et al, 2014 ).…”

Section: Biosynthesis and Functions Of Major Lmw Thiol-redox Buffers mentioning

confidence: 99%

Redox regulation by reversible protein S-thiolation in bacteria

2015

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Low molecular weight (LMW) thiols function as thiol-redox buffers to maintain the reduced state of the cytoplasm. The best studied LMW thiol is the tripeptide glutathione (GSH) present in all eukaryotes and Gram-negative bacteria. Firmicutes bacteria, including Bacillus and Staphylococcus species utilize the redox buffer bacillithiol (BSH) while Actinomycetes produce the related redox buffer mycothiol (MSH). In eukaryotes, proteins are post-translationally modified to S-glutathionylated proteins under conditions of oxidative stress. S-glutathionylation has emerged as major redox-regulatory mechanism in eukaryotes and protects active site cysteine residues against overoxidation to sulfonic acids. First studies identified S-glutathionylated proteins also in Gram-negative bacteria. Advances in mass spectrometry have further facilitated the identification of protein S-bacillithiolations and S-mycothiolation as BSH- and MSH-mixed protein disulfides formed under oxidative stress in Firmicutes and Actinomycetes, respectively. In Bacillus subtilis, protein S-bacillithiolation controls the activities of the redox-sensing OhrR repressor and the methionine synthase MetE in vivo. In Corynebacterium glutamicum, protein S-mycothiolation was more widespread and affected the functions of the maltodextrin phosphorylase MalP and thiol peroxidase (Tpx). In addition, novel bacilliredoxins (Brx) and mycoredoxins (Mrx1) were shown to function similar to glutaredoxins in the reduction of BSH- and MSH-mixed protein disulfides. Here we review the current knowledge about the functions of the bacterial thiol-redox buffers glutathione, bacillithiol, and mycothiol and the role of protein S-thiolation in redox regulation and thiol protection in model and pathogenic bacteria.

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“… 1 For instance, S. aureus FosB is a Mn(II)-dependent enzyme that inactivates the antibiotic fosfomycin. 98 , 99 Many enzymes involved in general metabolism, including S. Typhimurium propionate kinase and the E. coli lactonase UlaG, are active with added Mn(II). 100 , 101 A potential mycobacterial virulence factor and putative oxidase named Rv0223 requires a Mn/Fe cofactor for activity.…”

Section: Microbial Manganese Enzymes Contribute To Pathogenesismentioning

confidence: 99%

Manganese and Microbial Pathogenesis: Sequestration by the Mammalian Immune System and Utilization by Microorganisms

2015

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Bacterial and fungal pathogens cause a variety of infectious diseases and constitute a significant threat to public health. The human innate immune system represents the first line of defense against pathogenic microbes and employs a range of chemical artillery to combat these invaders. One important mechanism of innate immunity is the sequestration of metal ions that are essential nutrients. Manganese is one nutrient that is required for many pathogens to establish an infective lifestyle. This review summarizes recent advances in the role of manganese in the host–pathogen interaction and highlights Mn(II) sequestration by neutrophil calprotectin as well as how bacterial acquisition and utilization of manganese enables pathogenesis.

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Structure and Function of the Genomically Encoded Fosfomycin Resistance Enzyme, FosB, from Staphylococcus aureus

Cited by 45 publications

References 43 publications

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus

Redox regulation by reversible protein S-thiolation in bacteria

Manganese and Microbial Pathogenesis: Sequestration by the Mammalian Immune System and Utilization by Microorganisms

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