The Role of mprF Mutations in Seesaw Effect of Daptomycin-Resistant Methicillin-Resistant Staphylococcus aureus Isolates
| Autor: | Feng Zhao, Feiteng Zhu, Dandan Wu, Yunsong Yu, Shengnan Jiang, Haiping Wang, Junxiong Zhang, Hemu Zhuang, Lu Sun, Xiang Wei, Chen Yan, Rushuang Yan, Shujuan Ji |
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| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Mutation medicine.drug_class Point mutation Antibiotics Clone (cell biology) biochemical phenomena metabolism and nutrition Biology medicine.disease_cause Methicillin-resistant Staphylococcus aureus Microbiology Complementation Infectious Diseases Staphylococcus aureus medicine Pharmacology (medical) Daptomycin medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 66 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.01295-21 |
| Popis: | The emergence of daptomycin-resistant (DAP-R) Staphylococcus aureus strains has become a global problem. Point mutations in mprF are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant S. aureus (MRSA) strains associated with DAP resistance and the "see-saw effect" of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated mprF alleles from clone complexes (CC) 5 and 59 to explore the "see-saw effect" and the combination effect of DAP plus beta-lactams. Through construction of mprF deletion and complementation strains of SA268, we determined that mprF-S295A, mprF-S337L and one novel mutation of mprF-I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type mprF cloned from a DAP-susceptible (DAP-S) strain, these three mprF mutations conferred the "see-saw effect" to distinct beta-lactams in the SA268ΔmprF strains and mutated-mprF (I348del and S337L) did not alter the cell surface positive charge (P > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the "see-saw effect" was found to be associated with distinct mutated mprF alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mprF mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections. |
| Databáze: | OpenAIRE |
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