Abstract
BackgroundViridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens. They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Such alterations in phospholipid biosynthesis will modify carbon flow and change the bacterial metabolic status. To determine the metabolic differences between daptomycin-susceptible and non-susceptible bacteria, the physiology and metabolomes of S. mitis-oralis strains 351 (daptomycin-susceptible) and 351-D10 (daptomycin non-susceptible) were analyzed. S. mitis-oralis strain 351-D10 was made daptomycin non-susceptible through serial passage in the presence of daptomycin.ResultsDaptomycin non-susceptible S. mitis-oralis had significant alterations in glucose catabolism and a re-balancing of the redox status through amino acid biosynthesis relative to daptomycin susceptible S. mitis-oralis. These changes were accompanied by a reduced capacity to generate biomass, creating a fitness cost in exchange for daptomycin non-susceptibility.ConclusionsS. mitis-oralis metabolism is altered in daptomycin non-susceptible bacteria relative to the daptomycin susceptible parent strain. As demonstrated in Staphylococcus aureus, inhibiting the metabolic changes that facilitate the transition from a daptomycin susceptible state to a non-susceptible one, inhibits daptomycin non-susceptibility. By preventing these metabolic adaptations in S. mitis-oralis, it should be possible to deter the formation of daptomycin non-susceptibility.
Highlights
Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens
In S. mitis-oralis, daptomycin non-susceptibility is associated with mutations in cdsA and pgsA [8, 9], genes involved in biosynthesis of membrane phospholipids [10]
Daptomycin non-susceptibility alters growth of S. mitis The transition of S. mitis-oralis strain 351 from a daptomycin-susceptible state to a non-susceptible state during serial passage was accompanied by a decreased growth rate (351 and 351-D10; 29 ± 1 min and 39 ± 1.5 min, respectively) and a decreased growth yield/biomass (Fig. 1a and Supplemental Fig. 1)
Summary
Viridans group streptococci of the Streptococcus mitis-oralis subgroup are important endovascular pathogens They can rapidly develop high-level and durable non-susceptibility to daptomycin both in vitro and in vivo upon exposure to daptomycin. Two consistent genetic adaptations associated with this phenotype (i.e., mutations in cdsA and pgsA) lead to the depletion of the phospholipids, phosphatidylglycerol and cardiolipin, from the bacterial membrane. Among the viridans group streptococci, the S. mitis-oralis subgroup (i.e., S. mitis, S. oralis, S. gordonii and S. parasanguinis) are the predominant IE etiologies This sub-group is therapeutically problematic, as between 10 and 40% of strains exhibit resistance to penicillins and/or cephalosporins, including ceftriaxone [3, 4]. In S. mitis-oralis, daptomycin non-susceptibility is associated with mutations in cdsA and pgsA [8, 9], genes involved in biosynthesis of membrane phospholipids [10]. These mutations in daptomycin non-susceptible S. mitis-oralis strains result in the loss of phosphotidylglycerol and cardiolipin from the membrane
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
