Heterogeneity of mprF Sequences in Methicillin-Resistant Staphylococcus aureus Clinical Isolates: Role in Cross-Resistance between Daptomycin and Host Defense Antimicrobial Peptides
Open Access
- 1 December 2014
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 58 (12), 7462-7467
- https://doi.org/10.1128/aac.03422-14
Abstract
Over the past several years, single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) have been proposed to be associated with a gain-of-function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) in Staphylococcus aureus . We investigated the frequencies of SNPs within the mprF ORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistant S. aureus (MRSA) isolates of the clonal complex 5 genotype were used. In addition to mprF SNPs and DAP-HDP cross-resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i) mprF expression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of ≤1 μg/ml) exhibited mprF SNPs, occasionally with high-level mprF sequence variation from the genotype reference strain. However, none of these SNPs were localized to well-chronicled mprF hot spot locations associated with DAP-R in S. aureus . In contrast, all 8 DAP-R isolates demonstrated SNPs within such known mprF hot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhanced mprF expression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array of mprF SNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrent mprF dysregulation, were associated with the DAP-R phenotype.Keywords
This publication has 33 references indexed in Scilit:
- VraSR Two-Component Regulatory System Contributes to mprF -Mediated Decreased Susceptibility to Daptomycin in In Vivo -Selected Clinical Strains of Methicillin-Resistant Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2012
- An Association Between Bacterial Genotype Combined With a High-Vancomycin Minimum Inhibitory Concentration and Risk of Endocarditis in Methicillin-Resistant Staphylococcus aureus Bloodstream InfectionClinical Infectious Diseases, 2011
- In Vitro Cross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus IsolatesAntimicrobial Agents and Chemotherapy, 2011
- Correlation of Daptomycin Resistance in a Clinical Staphylococcus aureus Strain with Increased Cell Wall Teichoic Acid Production and d -AlanylationAntimicrobial Agents and Chemotherapy, 2011
- Lysyl-Phosphatidylglycerol Attenuates Membrane Perturbation Rather than Surface Association of the Cationic Antimicrobial Peptide 6W-RP-1 in a Model Membrane System: Implications for Daptomycin ResistanceAntimicrobial Agents and Chemotherapy, 2010
- Cell Wall Thickening Is Not a Universal Accompaniment of the Daptomycin Nonsusceptibility Phenotype in Staphylococcus aureus : Evidence for Multiple Resistance MechanismsAntimicrobial Agents and Chemotherapy, 2010
- Factors Influencing Time to Vancomycin‐Induced Clearance of Nonendocarditis Methicillin‐ResistantStaphylococcus aureusBacteremia: Role of Platelet Microbicidal Protein Killing andagrGenotypesThe Journal of Infectious Diseases, 2010
- Enhanced Expression ofdltABCDIs Associated with the Development of Daptomycin Nonsusceptibility in a Clinical Endocarditis Isolate ofStaphylococcus aureusThe Journal of Infectious Diseases, 2009
- Interaction of the GraRS Two-Component System with the VraFG ABC Transporter To Support Vancomycin-Intermediate Resistance in Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2007
- Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureusAntimicrobial Agents and Chemotherapy, 2006