Premium
Streptococcus mitis and Streptococcus oralis Mutate an ‘Essential’” Gene Upon Exposure to Daptomycin
Author(s) -
Adams Hannah,
Joyce Luke,
Guan Ziqiang,
Akins Ronda,
Palmer Kelli
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.777.17
Subject(s) - streptococcus mitis , streptococcus oralis , microbiology and biotechnology , daptomycin , staphylococcus aureus , streptococcus pneumoniae , streptococcus , enterococcus , biology , methicillin resistant staphylococcus aureus , vancomycin , antibiotics , chemistry , bacteria , genetics
Viridans Group Streptococci (VGS) are Gram‐positive opportunistic pathogens which are part of the normal gastrointestinal and oropharyngeal flora. Clinically, VGS are causative agents of infective endocarditis and bacteremia in immuno‐suppressed and neutropenic patients. Multidrug resistance (MDR) is on the rise within the VGS, as many isolates are now resistant to ampicillin, fluoroquinolones and macrolides. As with most pathogens, novel treatment methods are needed to combat VGS infections. Daptomycin (DAP) is a lipopeptide antibiotic with bactericidal activity against Gram‐positive bacteria. DAP has been shown to be effective against MDR infections, including methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant enterococci (VRE). Previously, Akins et al obtained DAP‐resistant VGS strains after overnight exposure to DAP in a simulated endocardial vegetation model. Using two Streptococcus oralis strains (1647 and 1648) and one Streptococcus mitis strain (1643), we demonstrated that DAP resistance up to 256 μg/mL could be obtained overnight in standard laboratory conditions with a single 4 μg/mL DAP exposure. Using whole genome sequencing, we identified loss‐of‐function mutations in the gene cdsA for all three VGS strains. These mutations reverted when the resistant strains were serially passaged until susceptibility was observed. cdsA is essential in better studied streptococci such as S. pneumoniae and S. pyogenes . CdsA is responsible for catalyzing the conversion of phosphatidic acid (PA) into cytidine diphosphate‐diacylglycerol (CDP‐DAG), which is a key intermediate in the biosynthesis of major phospholipids found in bacterial membranes, including phosphatidylglycerol (PG) and cardiolipin (CL). Using liquid chromatography/mass spectrometry (LC/MS), we confirmed CdsA loss‐of‐function mutations in each of the DAP‐resistant strains, as evidenced by the absence of PG and CL, and the accumulation of PA in these strains. In addition, we have identified a new glycolipid in our S. mitis strain. These data show that DAP resistance proceeds through a novel adaptive pathway in S. mitis and S. oralis as compared to MRSA and VRE; that cdsA is non‐essential in these VGS and that adaptation to DAP results in altered membrane lipid composition in these organisms. Support or Funding Information Start‐up funds from UT‐Dallas to KP and GM069338 and EY023666 from NIH to ZG.