title: Phenotypic and genotypic correlates of daptomycin-resistant methicillin-susceptible Staphylococcus aureus clinical isolates.
abstract: Daptomycin (DAP) has potent activity in vitro and in vivo against both methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains. DAP-resistance (DAP-R) in S. aureus has been mainly observed in MRSA strains, and has been linked to single nucleotide polymorphisms (SNPs) within the mprF gene leading to altered cell membrane (CM) phospholipid (PL) profiles, enhanced positive surface charge, and changes in CM fluidity. The current study was designed to delineate whether these same genotypic and phenotypic perturbations are demonstrated in clinically-derived DAP-R MSSA strains. We used three isogenic DAP-susceptible (DAP-S)/DAP-R strainpairs and compared: (i) presence of mprF SNPs, (ii) temporal expression profiles of the two key determinants (mprF and dltABCD) of net positive surface charge, (iii) increased production of mprF-dependent lysinylated-phosphatidylglycerol (L-PG), (iv) positive surface charge assays, and (v) susceptibility to cationic host defense peptides (HDPs) of neutrophil and platelet origins. Similar to prior data in MRSA, DAP-R (vs DAP-S) MSSA strains exhibited hallmark hot-spot SNPs in mprF, enhanced and dysregulated expression of both mprF and dltA, L-PG overproduction, HDP resistance and enhanced positive surface charge profiles. However, in contrast to most DAP-R MRSA strains, there were no changes in CM fluidity seen. Thus, charge repulsion via mprF-and dlt-mediated enhancement of positive surface charge may be the main mechanism to explain DAP-R in MSSA strains.
authors.affiliation: School of Bioresources and Bioscience, Chung-Ang University, Gyeonggi-do, 17546, Republic of Korea.
authors.forename: Kyoung-Mi
authors.initials: KM
authors.lastname: Kang
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.|The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Nagendra N
authors.initials: NN
authors.lastname: Mishra
authors.affiliation: Department of Veterinary Microbiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Kun Taek
authors.initials: KT
authors.lastname: Park
authors.affiliation: School of Bioresources and Bioscience, Chung-Ang University, Gyeonggi-do, 17546, Republic of Korea.
authors.forename: Gi-Yong
authors.initials: GY
authors.lastname: Lee
authors.affiliation: Department of Veterinary Microbiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Park
authors.affiliation: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.|The David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Bayer
authors.affiliation: School of Bioresources and Bioscience, Chung-Ang University, Gyeonggi-do, 17546, Republic of Korea. soojin@cau.ac.kr.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Yang
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D017576:Daptomycin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D015964:Gene Expression Regulation, Bacterial; D005838:Genotype; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D008712:Methicillin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D017576:Daptomycin; D008712:Methicillin
keywords: Staphylococcus aureus; daptomycin resistance; host defense antimicrobial peptide; mprF; single nucleotide polymorphism (SNP)