Meeting the Challenges of Methicillin‐Resistant<i>Staphylococcus aureus</i>with Outpatient Parenteral Antimicrobial Therapy

Tice, Alan D.; Rehm, Susan J.

doi:10.1086/653517

Cited by 16 publications

(10 citation statements)

References 38 publications

(56 reference statements)

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“…(A summary of the key characteristics of each service can be found in Appendix 2, Table 38.) The professions of those interviewed included nurse specialists (3), microbiologists (6), pharmacists (2) and infection specialists including joint qualified (9).…”

Section: Sample Characteristicsmentioning

confidence: 99%

The Community IntraVenous Antibiotic Study (CIVAS): a mixed-methods evaluation of patient preferences for and cost-effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy

Minton

Czoski-Murray

Meads

et al. 2017

Health Serv Deliv Res

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Section: Sample Characteristicsmentioning

confidence: 99%

The Community IntraVenous Antibiotic Study (CIVAS): a mixed-methods evaluation of patient preferences for and cost-effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy

Minton

Czoski-Murray

Meads

et al. 2017

Health Serv Deliv Res

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“…Pathogenic bacterial infections, such as those from Staphylococcus aureus, are a leading cause of life-threatening human diseases, including pneumonia, meningitis, and osteomyelitis (Ippolito et al, 2010). Some strains have proven remarkably successful at overcoming almost all host immune and antibiotic strategies, thereby limiting therapeutic options (Gordon and Lowy, 2008;Tice and Rehm, 2010). In particular, infections of S. aureus that are resistant to vancomycin or multiantibiotic strategies are now endemic in many health care institutions and communities (Cataldo et al, 2010;Ippolito et al, 2010;Murray, 2000), and there is a need to explore new therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Bacterial ABC Transporter Inhibition by an Antibody Fragment

Ahuja¹,

Rougé²,

Swem³

et al. 2015

Structure

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Bacterial ATP-binding cassette (ABC) importers play critical roles in nutrient acquisition and are potential antibacterial targets. However, structural bases for their inhibition are poorly defined. These pathways typically rely on substrate binding proteins (SBPs), which are essential for substrate recognition, delivery, and transporter function. We report the crystal structure of a Staphylococcus aureus SBP for Mn(II), termed MntC, in complex with FabC1, a potent antibody inhibitor of the MntABC pathway. This pathway is essential and highly expressed during S. aureus infection and facilitates the import of Mn(II), a critical cofactor for enzymes that detoxify reactive oxygen species (ROS). Structure-based functional studies indicate that FabC1 sterically blocks a structurally conserved surface of MntC, preventing its interaction with the MntB membrane importer and increasing wild-type S. aureus sensitivity to oxidative stress by more than 10-fold. The results define an SBP blocking mechanism as the basis for ABC importer inhibition by an engineered antibody fragment.

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“…Its prevalence and adaptability in both community and hospital environment makes healthy patients and immune-deficient patients [2] at high risk of infection [3], [4]. Its continued pathogenicity and virulence [5], [6] causes invasive infection in bloodstream [7], essential organs, and tissues [8], [9], therefore leads to severe clinical presentations and high mortality rate [4], [10]. This is primarily due to the high incidence of methicillin-resistance that has failed almost all available antibiotics [11].…”

Section: Introductionmentioning

confidence: 99%

Targeting RNA Polymerase Primary σ70 as a Therapeutic Strategy against Methicillin-Resistant Staphylococcus aureus by Antisense Peptide Nucleic Acid

et al. 2012

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BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) causes threatening infection-related mortality worldwide. Currently, spread of multi-drug resistance (MDR) MRSA limits therapeutic options and requires new approaches to “druggable” target discovery, as well as development of novel MRSA-active antibiotics. RNA polymerase primary σ70 (encoded by gene rpoD) is a highly conserved prokaryotic factor essential for transcription initiation in exponentially growing cells of diverse S. aureus, implying potential for antisense inhibition.Methodology/Principal FindingsBy synthesizing a serial of cell penetrating peptide conjugated peptide nucleic acids (PPNAs) based on software predicted parameters and further design optimization, we identified a target sequence (234 to 243 nt) within rpoD mRNA conserved region 3.0 being more sensitive to antisense inhibition. A (KFF)3K peptide conjugated 10-mer complementary PNA (PPNA2332) was developed for potent micromolar-range growth inhibitory effects against four pathogenic S. aureus strains with different resistance phenotypes, including clinical vancomycin-intermediate resistance S. aureus and MDR-MRSA isolates. PPNA2332 showed bacteriocidal antisense effect at 3.2 fold of MIC value against MRSA/VISA Mu50, and its sequence specificity was demonstrated in that PPNA with scrambled PNA sequence (Scr PPNA2332) exhibited no growth inhibitory effect at higher concentrations. Also, PPNA2332 specifically interferes with rpoD mRNA, inhibiting translation of its protein product σ70 in a concentration-dependent manner. Full decay of mRNA and suppressed expression of σ70 were observed for 40 µM or 12.5 µM PPNA2332 treatment, respectively, but not for 40 µM Scr PPNA2332 treatment in pure culture of MRSA/VISA Mu50 strain. PPNA2332 (≥1 µM) essentially cleared lethal MRSA/VISA Mu50 infection in epithelial cell cultures, and eliminated viable bacterial cells in a time- and concentration- dependent manner, without showing any apparent toxicity at 10 µM.ConclusionsThe present result suggested that RNAP primary σ70 is a very promising candidate target for developing novel antisense antibiotic to treat severe MRSA infections.

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Meeting the Challenges of Methicillin‐ResistantStaphylococcus aureuswith Outpatient Parenteral Antimicrobial Therapy

Cited by 16 publications

References 38 publications

The Community IntraVenous Antibiotic Study (CIVAS): a mixed-methods evaluation of patient preferences for and cost-effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy

The Community IntraVenous Antibiotic Study (CIVAS): a mixed-methods evaluation of patient preferences for and cost-effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy

Structural Analysis of Bacterial ABC Transporter Inhibition by an Antibody Fragment

Targeting RNA Polymerase Primary σ70 as a Therapeutic Strategy against Methicillin-Resistant Staphylococcus aureus by Antisense Peptide Nucleic Acid

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