Yingchun Xu | Search PubMed

PubMed2025

In vitro activity of contezolid and other comparators against clinical Staphylococcus and Enterococcus: a multicenter study in China.

OBJECTIVE: To evaluate the in vitro activity of contezolid against clinical Staphylococcus and Enterococcus isolates from across China, and compare its performance with linezolid and other key agents. METHODS: A total of 2510 non-duplicate Gram-positive cocci isolates were collected from 70 hospitals in seven Chinese regions. Minimum inhibitory concentrations (MICs) were determined using broth microdilution (BMD) per CLSI guidelines. MIC50/90 values, susceptibility rates, cumulative MIC curves and MIC distribution agreement between contezolid and linezolid were assessed. Linezolid-resistant isolates and contezolid-resistant isolates-defined as those based on CLSI 2025 linezolid breakpoints-underwent whole-genome sequencing and comprehensive screening for known oxazolidinone resistance determinants, including acquired resistance genes, 23S rRNA mutations and amino acid substitutions in ribosomal proteins L3, L4 and L22. RESULTS: Contezolid exhibited potent in vitro activity, with >99% of isolates inhibited at ≤4 mg/L and showed lower MIC50/90 than linezolid, with a consistently left-shifted cumulative MIC distribution. Cohen's kappa analysis supporting enhanced activity of contezolid. Notably, we report for the first time clinical isolates with contezolid MICs up to 16 mg/L. Whole-genome analysis of 14 linezolid-resistant isolates (including five resistant to contezolid) revealed universal presence of optrA, cfr, fexA and other resistance genes, alongside domain V 23S rRNA mutations and substitutions in ribosomal proteins L3 and L4, supporting a shared genetic basis and potential cross-resistance between the two agents. CONCLUSIONS: Contezolid demonstrated potent and consistent activity against drug-resistant Gram-positive cocci, supporting its potential as a therapeutic alternative to linezolid. Further studies are needed to confirm resistance mechanisms and clinical utility.

Microbial Sensitivity Tests↗

PubMed2024

Adaptation for Staphylococcus aureus to hosts via insertion mutation in the accessory gene regulator agrC gene: decreased virulence and enhanced persistence capacity.

UNLABELLED: Staphylococcus aureus is an important human pathogen due to its vast array of virulence factors regulated by multiple regulatory mechanisms, including the accessory gene regulator. In this study, two S. aureus strains were simultaneously isolated from the blood of a febrile patient, belonging to the same clone, designated as 23H with a complete hemolytic phenotype, and 23B, exhibiting an incomplete hemolytic phenotype. The genomic comparison between strains 23B and 23H revealed that 23B had a single adenine base insertion at position 923 in the agrC gene, leading to a functional loss of the encoded AgrC. Experimental findings showed that strain 23B had decreased hemolytic activity, lower cytotoxicity against human alveolar epithelial A549 cells and in the Galleria mellonella model, and a reduced ability to survive intracellularly after infecting macrophages, in comparison to 23H. Conversely, 23B exhibited enhanced biofilm formation, greater adherence to A549 cells, and increased persistence in the face of vancomycin and daptomycin treatment. Transcriptomic analysis revealed that 23B upregulated surface protein-encoding genes while simultaneously reducing the expression levels of virulence factors, highlighting the intricate regulatory adjustments facilitating its persistence and reducing pathogenic potential. ATP assay results indicated that 23B maintained elevated ATP levels during the exponential phase yet exhibited reduced levels in the stationary phase when compared with 23H. Our findings suggested that the mutation in the agrC gene of S. aureus results in diminished virulence but markedly enhances persistence. This mutated strain warrants clinical attention because it may lead to treatment failures and persist in patients. IMPORTANCE: In clinical antimicrobial therapy, bacterial strains often develop resistance to antimicrobial agents. Additionally, mutations in their gene regulatory networks can increase their persistence, especially in immunocompromised patients. This study identified an insertion mutation in the accessory gene regulator, agrC gene, carried by a Staphylococcus aureus strain isolated from the blood of a febrile patient, leading to the functional loss of AgrC. Further research revealed that despite the reduced virulence of the mutated strain, it significantly bolstered the capacity to adapt and endure within the host during prolonged infections. This was evidenced by increased adhesion and biofilm formation capabilities, development of antimicrobial tolerance, and decreased ATP levels linked to persistence. Therefore, monitoring these mutations in S. aureus is crucial clinically, as they can complicate treatment strategies.

Staphylococcus aureus↗