The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A

Jousselin, Ambre; Manzano, C.; Biette, Alexandra; Reed, Patricia; Pinho, Mariana G.; Rosato, Adriana E.; Kelley, William L.; Renzoni, Adriana

doi:10.1128/aac.02333-15

Cited by 65 publications

(74 citation statements)

References 53 publications

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“…SAUSA300_1790 (prsA) encodes a parvulin-like protein with a secretion signal sequence and is predicted to be a cell wall-associated lipoprotein. A number of recent studies have implicated S. aureus PrsA in resistance to antibiotics (13,14); however, it is unknown what role, if any, it has in protein secretion. SAUSA300_0857 (which we named ppiB due to its homology to ppiB of Bacillus subtilis) is an uncharacterized gene putatively encoding a PPIase with homology to the cyclophilin family.…”

Section: Resultsmentioning

confidence: 99%

“…A number of recent reports have demonstrated a role for S. aureus PrsA in antibiotic resistance (13,14). One proposed mechanism that contributes to methicillin resistance in MRSA strains is via export and/or folding of newly synthesized penicillin-binding protein 2A (PBP2A).…”

Section: Discussionmentioning

confidence: 99%

“…Although PPIases have been studied in other bacteria, their role in S. aureus is not well understood. Recently, mutation of prsA was shown to affect antibiotic resistance in S. aureus (13,14); however, its role in protein secretion is unknown, and no studies have been performed on additional S. aureus PPIases.…”

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confidence: 99%

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An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

et al. 2017

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Staphylococcus aureus is an important human pathogen that relies on a large repertoire of secreted and cell wall-associated proteins for pathogenesis. Consequently, the ability of the organism to cause disease is absolutely dependent on its ability to synthesize and successfully secrete these proteins. In this study, we investigate the role of peptidyl-prolyl cis/trans isomerases (PPIases) on the activity of the S. aureus secreted virulence factor nuclease (Nuc). We identify a staphylococcal cyclophilin-type PPIase (PpiB) that is required for optimal activity of Nuc. Disruption of ppiB results in decreased nuclease activity in culture supernatants; however, the levels of Nuc protein are not altered, suggesting that the decrease in activity results from misfolding of Nuc in the absence of PpiB. We go on to demonstrate that PpiB exhibits PPIase activity in vitro, is localized to the bacterial cytosol, and directly interacts with Nuc in vitro to accelerate the rate of Nuc refolding. Finally, we demonstrate an additional role for PpiB in S. aureus hemolysis and demonstrate that the S. aureus parvulin-type PPIase PrsA also plays a role in the activity of secreted virulence factors. The deletion of prsA leads to a decrease in secreted protease and phospholipase activity, similar to that observed in other Gram-positive pathogens. Together, these results demonstrate, for the first time to our knowledge, that PPIases play an important role in the secretion of virulence factors in S. aureus.IMPORTANCE Staphylococcus aureus is a highly dangerous bacterial pathogen capable of causing a variety of infections throughout the human body. The ability of S. aureus to cause disease is largely due to an extensive repertoire of secreted and cell wall-associated proteins, including adhesins, toxins, exoenzymes, and superantigens. These virulence factors, once produced, are typically transported across the cell membrane by the secretory (Sec) system in a denatured state. Consequently, once outside the cell, they must refold into their active form. This step often requires the assistance of bacterial folding proteins, such as PPIases. In this work, we investigate the role of PPIases in S. aureus and uncover a cyclophilin-type enzyme that assists in the folding/refolding of staphylococcal nuclease.KEYWORDS cyclophilin, Nuc, PI-PLC, PPIase, parvulin, PpiB, PrsA, Staphylococcus aureus, nuclease, protease T he proline peptide bond is unique in nature in that both the cis and trans forms can occur in vivo, with the cis conformation existing approximately 6.5% of the time (1). In contrast, for all other naturally occurring amino acids, steric hindrance between side chains precludes the cis form and overwhelmingly favors the trans form (2). The presence of both the cis and trans forms of proline peptide bonds has important consequences for protein tertiary structure. In certain cases, the isomerization state of

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

et al. 2017

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“…We have previously established a role for the lipoprotein PrsA as an important mediator of both glycopeptide and oxacillin resistance, with the latter occurring through its effect on the potential proper maturation of PBP 2a (13,14). A consideration of MprF and the biosynthesis of lipoproteins, such as PrsA, suggests a plausible model to explain the seesaw effect linking DAP nonsusceptibility and decreased resistance to certain antistaphylococcal ␤-lactams in MRSA strains (Fig.…”

Section: Discussionmentioning

confidence: 99%

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Renzoni

Kelley

Rosato

et al. 2017

Antimicrob Agents Chemother

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Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most difficult to treat in clinical settings due to the resistance of MRSA to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. The decreased susceptibility to DAP (DAP resistance [DAP r ]) reported in MRSA is frequently accompanied by a paradoxical decrease in ␤-lactam resistance, a process known as the "seesaw effect." Despite the observed discordance in resistance phenotypes, the combination of DAP and ␤-lactams has been proven to be clinically effective for the prevention and treatment of infections due to DAP r MRSA strains. However, the mechanisms underlying the interactions between DAP and ␤-lactams are largely unknown. In the study described here, we studied the role of mprF with DAP-induced mutations in ␤-lactam sensitization and its involvement in the effective killing by the DAP-oxacillin (OXA) combination. DAP-OXA-mediated effects resulted in cell wall perturbations, including changes in peptidoglycan insertion, penicillin-binding protein 2 (PBP 2) delocalization, and reduced membrane amounts of PBP 2a, despite the increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications that result in impairment of PrsA location and chaperone functions, both of which are essential for PBP 2a maturation, the key determinant of ␤-lactam resistance. These observations provide for the first time evidence that synergistic effects between DAP and ␤-lactams involve PrsA posttranscriptional regulation of CM-associated PBP 2a.KEYWORDS MRSA, daptomycin, seesaw effect, ␤-lactams, PrsA, ␤-lactams S taphylococcus aureus has a proclivity for developing multidrug resistance (e.g., methicillin-resistant S. aureus [MRSA]), and infections with this pathogen result in enhanced attributable mortality (1). Since its FDA approval in 2003, the cyclic anionic lipopeptide antibiotic daptomycin (DAP), produced by Streptomyces roseosporus (2), has become the clinical mainstay of anti-MRSA therapy due to its potent staphylocidal

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“…According to Baiu & AL-Abdli (2015), due to antibiotics resistance, MRSA infections required more complicated treatment. Resistance due to mecA gene, which encodes an alternative Penicillin Binding Protein (PBP2a), prevents the action of beta lactam antibiotics (Jousselin et al, 2016). In addition, coagulase gene (Coa) is usually used to identify and compare S. aureus because it consists of 81-bp tandem repeats region at the 3' ends (Hookey et al, 1998).…”

Section: Methicillin Resistant S Aureus (Mrsa) and Coagulase Negativementioning

confidence: 99%

Detection of methicillin resistant Staphylococcus areus isolated from nasal carriage of health care workers by polymerase chain reaction

Alsulami¹,

Doghaither²

2017

JEBAS

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Methicillin resistant Staphylococcus aureus (MRSA) and coagulase negative Staphylococci (MRCoNS) are major health problems worldwide. There is a growing concern about the rapid rise in resistance of nosocomial infections to antimicrobial agents. The aim of the present study was to determine nasal colonization of MRSA and MRCoNS among healthcare workers (HCWs) in King Abdulaziz University hospital. A total of 100 respondents were selected for this study and were classified into two groups: HCWs group which included 50 technicians and nurses, and the control group which included 50 university students. Nasal swabs from anterior nares were cultured on selective media for the presence of mecA gene that is common to these bacteria. Polymerase chain reaction (PCR) and specific primers were used to determine mecA and coagulase gene (coa). The identified isolates were tested by restriction fragment length polymorphism (RFLP). Results of current study revealed that among 50 HCWs, 21 (42%) were nasal carriers for MRCoNS and 12 (24%) for MRSA. The control group was negative for MRSA and MRCoNS. The results of the current study will help in making decision to prevent the spread of infections among workers in the field of health care. KEYWORDS MRSA MRCoNS healthcare workersmecA gene

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The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A

Cited by 65 publications

References 53 publications

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

Molecular Bases Determining Daptomycin Resistance-Mediated Resensitization to β-Lactams (Seesaw Effect) in Methicillin-Resistant Staphylococcus aureus

Detection of methicillin resistant Staphylococcus areus isolated from nasal carriage of health care workers by polymerase chain reaction

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