Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures
The <i>Streptococcus mitis-oralis</i> subgroup of viridans group streptococci are important human pathogens. We previously showed that a substantial portion of <i>S. mitis-oralis</i> strains (>25%) are ‘destined’ to develop rapid, high-level, and stable daptomycin (DAP) re...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/7/1083 |
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| author | Nagendra N. Mishra Rodrigo de Paula Baptista Truc T. Tran Christian K. Lapitan Cristina Garcia-de-la-Maria Jose M. Miró Richard A. Proctor Arnold S. Bayer |
| author_facet | Nagendra N. Mishra Rodrigo de Paula Baptista Truc T. Tran Christian K. Lapitan Cristina Garcia-de-la-Maria Jose M. Miró Richard A. Proctor Arnold S. Bayer |
| author_sort | Nagendra N. Mishra |
| collection | DOAJ |
| description | The <i>Streptococcus mitis-oralis</i> subgroup of viridans group streptococci are important human pathogens. We previously showed that a substantial portion of <i>S. mitis-oralis</i> strains (>25%) are ‘destined’ to develop rapid, high-level, and stable daptomycin (DAP) resistance (DAP-R) during DAP exposures in vitro. Such DAP-R is often accompanied by perturbations in distinct membrane phenotypes and metabolic pathways. The current study evaluated two <i>S. oralis</i> bloodstream isolates, 73 and 205. Strain 73 developed stable, high-level DAP-R (minimum inhibitory concentration [MIC] > 256 µg/mL) within 2 days of in vitro DAP passage (“high level” DAP-R [HLDR]). In contrast, strain 205 evolved low-level and unstable DAP-R (MIC = 8 µg/mL) under the same exposure conditions in vitro (“non-HLDR”). Comparing the parental 73 vs. 73-D2 (HLDR) strain-pair, we observed the 73-D2 had the following major differences: (i) altered cell membrane (CM) phospholipid profiles, featuring the disappearance of phosphatidylglycerol (PG) and cardiolipin (CL), with accumulation of the PG-CL pathway precursor, phosphatidic acid (PA); (ii) enhanced CM fluidity; (iii) increased DAP surface binding; (iv) reduced growth rates; (v) decreased glucose utilization and lactate accumulation; and (vi) increased enzymatic activity within the glycolytic (i.e., lactate dehydrogenase [LDH]) and lipid biosynthetic (glycerol-3-phosphate dehydrogenase [GPDH]) pathways. In contrast, the 205 (non-HLDR) strain-pair did not show these same phenotypic or metabolic changes over the 2-day DAP exposure. WGS analyses confirmed the presence of mutations in genes involved in the above glycolytic and phospholipid biosynthetic pathways in the 73-D2 passage variant. These data suggest that <i>S. oralis</i> strains which are ‘destined’ to rapidly develop HLDR do so via a conserved cadre of genotypic, membrane phenotypic, and metabolic adaptations. |
| first_indexed | 2024-03-11T01:22:36Z |
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| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T01:22:36Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-7e3c229eb7074fa39d245455204e823e2023-11-18T18:01:56ZengMDPI AGAntibiotics2079-63822023-06-01127108310.3390/antibiotics12071083Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin ExposuresNagendra N. Mishra0Rodrigo de Paula Baptista1Truc T. Tran2Christian K. Lapitan3Cristina Garcia-de-la-Maria4Jose M. Miró5Richard A. Proctor6Arnold S. Bayer7Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 West Carson St. MRL Bldg. Room 224, Torrance, CA 90502, USACenter for Infectious Diseases, Houston Methodist Research Institute, Houston, TX 77030, USACenter for Infectious Diseases, Houston Methodist Research Institute, Houston, TX 77030, USADivision of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 West Carson St. MRL Bldg. Room 224, Torrance, CA 90502, USAInfectious Diseases Service, Hospital Clinic—IDIBAPS, University of Barcelona, 08036 Barcelona, SpainCIBERINFEC, Instituto de Salud Carlos III, 28220 Madrid, SpainThe Department of Medicine, University of Wisconsin School of Medicine, Madison, WI 53705, USADivision of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, 1124 West Carson St. MRL Bldg. Room 224, Torrance, CA 90502, USAThe <i>Streptococcus mitis-oralis</i> subgroup of viridans group streptococci are important human pathogens. We previously showed that a substantial portion of <i>S. mitis-oralis</i> strains (>25%) are ‘destined’ to develop rapid, high-level, and stable daptomycin (DAP) resistance (DAP-R) during DAP exposures in vitro. Such DAP-R is often accompanied by perturbations in distinct membrane phenotypes and metabolic pathways. The current study evaluated two <i>S. oralis</i> bloodstream isolates, 73 and 205. Strain 73 developed stable, high-level DAP-R (minimum inhibitory concentration [MIC] > 256 µg/mL) within 2 days of in vitro DAP passage (“high level” DAP-R [HLDR]). In contrast, strain 205 evolved low-level and unstable DAP-R (MIC = 8 µg/mL) under the same exposure conditions in vitro (“non-HLDR”). Comparing the parental 73 vs. 73-D2 (HLDR) strain-pair, we observed the 73-D2 had the following major differences: (i) altered cell membrane (CM) phospholipid profiles, featuring the disappearance of phosphatidylglycerol (PG) and cardiolipin (CL), with accumulation of the PG-CL pathway precursor, phosphatidic acid (PA); (ii) enhanced CM fluidity; (iii) increased DAP surface binding; (iv) reduced growth rates; (v) decreased glucose utilization and lactate accumulation; and (vi) increased enzymatic activity within the glycolytic (i.e., lactate dehydrogenase [LDH]) and lipid biosynthetic (glycerol-3-phosphate dehydrogenase [GPDH]) pathways. In contrast, the 205 (non-HLDR) strain-pair did not show these same phenotypic or metabolic changes over the 2-day DAP exposure. WGS analyses confirmed the presence of mutations in genes involved in the above glycolytic and phospholipid biosynthetic pathways in the 73-D2 passage variant. These data suggest that <i>S. oralis</i> strains which are ‘destined’ to rapidly develop HLDR do so via a conserved cadre of genotypic, membrane phenotypic, and metabolic adaptations.https://www.mdpi.com/2079-6382/12/7/1083high-level daptomycin resistance<i>S. oralis</i>lipidsglycolysis |
| spellingShingle | Nagendra N. Mishra Rodrigo de Paula Baptista Truc T. Tran Christian K. Lapitan Cristina Garcia-de-la-Maria Jose M. Miró Richard A. Proctor Arnold S. Bayer Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures Antibiotics high-level daptomycin resistance <i>S. oralis</i> lipids glycolysis |
| title | Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures |
| title_full | Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures |
| title_fullStr | Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures |
| title_full_unstemmed | Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures |
| title_short | Membrane Phenotypic, Metabolic and Genotypic Adaptations of <i>Streptococcus oralis</i> Strains Destined to Rapidly Develop Stable, High-Level Daptomycin Resistance during Daptomycin Exposures |
| title_sort | membrane phenotypic metabolic and genotypic adaptations of i streptococcus oralis i strains destined to rapidly develop stable high level daptomycin resistance during daptomycin exposures |
| topic | high-level daptomycin resistance <i>S. oralis</i> lipids glycolysis |
| url | https://www.mdpi.com/2079-6382/12/7/1083 |
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