Characterization of a Novel Gene, srpA, Conferring Resistance to Streptogramin A, Pleuromutilins, and Lincosamides in Streptococcus suis
Autor: | Shaolin Wang, Kun Han, Jingpo Cui, Xiaoxia Qin, Zhanhui Wang, Lichao Ma, Lu Liu, Shuangyang Ding, Zhangqi Shen, Peng Zhang, Chaoyang Zhang |
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Rok vydání: | 2022 |
Předmět: |
Streptogramins
Environmental Engineering General Computer Science medicine.drug_class Materials Science (miscellaneous) General Chemical Engineering Antibiotics Energy Engineering and Power Technology Streptococcus suis 02 engineering and technology Biology 010402 general chemistry medicine.disease_cause 01 natural sciences Microbiology chemistry.chemical_compound Antibiotic resistance medicine Streptogramin A Lincosamides General Engineering 021001 nanoscience & nanotechnology biology.organism_classification 0104 chemical sciences chemistry Staphylococcus aureus Efflux 0210 nano-technology |
Zdroj: | Engineering. 9:85-94 |
ISSN: | 2095-8099 |
Popis: | Antimicrobial resistance is undoubtedly one of the greatest global health threats. The emergence of multidrug-resistant (MDR) gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (S. aureus), vancomycin-resistant Enterococcus faecium, and β-lactamase-resistant Streptococcus pneumonia, has severely limited our antibiotic arsenal. Numerous ribosome-targeting antibiotics, especially pleuromutilins, oxazolidinones, and streptogramins, are viewed as promising alternatives against aggressive MDR pathogens. In this study, we identified a new ABC-F family determinant, srpA, in Streptococcus suis (S. suis) by means of a comparative analysis of the whole-genome sequences of tiamulin-resistant and -sensitive bacteria. Functional cloning confirmed that the deduced gene can mediate cross-resistance to pleuromutilins, lincosamides, and streptogramin A in S. suis and S. aureus. A sequence alignment revealed that srpA shares the highest amino acid identity with Vga(E) (36%) and shows canonical characteristics of ABC-F family members. In SrpA-ribosome docked compounds, the extended loop region of SrpA approaches the valnemulin-binding pocket in the ribosome peptidyl-transferase center and competes with bound valnemulin. A detailed mutational analysis of the loop residues confirmed that this domain is crucial for SrpA activity, as substitutions or truncations of this region affect the efficiency and specificity of antibiotic resistance. Intracellular antibiotics accumulation indicated that SrpA does not act as an efflux pump, while a ribosome binding assay supported the protective effects of SrpA on the ribosome by preventing antibiotic binding as well as displacing bound drugs. These findings clarify the mechanisms underlying resistance to ribosomal antibiotics. |
Databáze: | OpenAIRE |
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