Phenotypic and genetic changes associated with the seesaw effect in MRSA strain N315 in a bioreactor model.
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Issue Date
1/24/2022
Authors
Mishra, Smruti*
Lasek-Nesselquist, Erica*
Mathur, Anarv*
Ma, Zhuo
Boonthaworn, Kanpong
O'Donnell, J Nicholas
Sui, Haixin
Pata, Janice D
McDonough, Kathleen A
Jayachandran, Pradeepa
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Abstract
Objectives: Over the past decade, daptomycin treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections has led to the emergence of daptomycin non-susceptible (DAP-NS) MRSA strains and a subsequent interest in combinatorial antibiotic therapies. We investigated the phenotypic and genetic changes associated with the seesaw effect, which describes the correlation between daptomycin resistance and increased beta-lactam susceptibility in DAP-NS MRSA and the reverse phenomenon of DAP-NS strains acquiring renewed susceptibility to daptomycin after beta-lactam exposure.
Methods: A continuous bioreactor model was used to study the effects of incremental doses of daptomycin followed by oxacillin on MRSA strain N315. MICs for daptomycin and oxacillin were determined for the bioreactor-derived samples. Transmission electron microscopy and cytochrome C binding assays were used to measure cell wall thickness and cell membrane charge, respectively, in the bioreactor-derived samples. Whole-genome sequencing was used to identify mutations associated with seesaw effect.
Results: While daptomycin resistance conferred enhanced susceptibility to oxacillin, oxacillin treatment of DAP-NS strains was accompanied by a lowered MIC for daptomycin. Additionally, there was a reduction in relative positive cell surface charge and cell wall thickness. However, the mutations acquired in our DAP-NS populations were not accompanied by additional genomic changes after treatment with oxacillin, implicating alternative mechanisms for the seesaw effect.
Conclusion: In this study, we successfully produced and characterized the seesaw effect in MRSA strain N315 in a unique bioreactor model.
Citation
Mishra S, Lasek-Nesselquist E, Mathur A, Ma Z, Boonthaworn K, O'Donnell N, Sui H, Pata JD, McDonough KA, Jayachandran P, Malik M. Phenotypic and genetic changes associated with the seesaw effect in MRSA strain N315 in a bioreactor model. J Glob Antimicrob Resist. 2022 Jan 24:S2213-7165(22)00017-0. doi: 10.1016/j.jgar.2022.01.013. Epub ahead of print. PMID: 35085792.
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