Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate &lt;em&gt;Staphylococcus aureus&lt;/em&gt;

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important clinical concern in patients, and is often associated with significant disease burden and metastatic infections. There is an increasing evidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) associated treatment failure. In this study, we aim to understand the molecular mechanism of teicoplanin resistant MRSA (TR-MRSA) and hVISA. A total of 482 MRSA isolates were investigated for these phenotypes. Of the tested isolates, 1% were identified as TR-MRSA, and 12% identified as hVISA. A highly diverse amino acid substitution was observed in tcaRAB, vraSR, and graSR genes in TR-MRSA and hVISA strains. Interestingly, 65% of hVISA strains had a D148Q mutation in the graR gene. However, none of the markers were reliable in differentiating hVISA from TR-MRSA. Significant pbp2 upregulation was noted in three TR-MRSA strains, which had teicoplanin MICs of 16 or 32 μg/ml, whilst significant pbp4 downregulation was not noted in these strains. In our study, multiple mutations were identified in the candidate genes, suggesting a complex evolutionary pathway involved in the development of TR-MRSA and hVISA strains.

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“…In S . aureus , tca A mutants contribute to the development of VISA [65, 66]. We identified novel mutations in tca A and tca B.…”

Section: Discussionmentioning

confidence: 99%

Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India

et al. 2019

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“…Various proteins contribute to the resistance of S. aureus against vancomycin (Lin et al, 2018 ). The proteomic pattern of isolates can be analyzed in a rapid, comprehensive, and cost-effective manner using matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) in clinical microbiology laboratories (Hrabák et al, 2013 ; Idelevich et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Rapid Detection of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Based on Matrix-Assisted Laser Desorption Ionization Time-of-Flight: Using a Machine Learning Approach and Unbiased Validation

et al. 2018

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Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is an emerging superbug with implicit drug resistance to vancomycin. Detecting hVISA can guide the correct administration of antibiotics. However, hVISA cannot be detected in most clinical microbiology laboratories because the required diagnostic tools are either expensive, time consuming, or labor intensive. By contrast, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) is a cost-effective and rapid tool that has potential for providing antibiotics resistance information. To analyze complex MALDI-TOF mass spectra, machine learning (ML) algorithms can be used to generate robust hVISA detection models. In this study, MALDI-TOF mass spectra were obtained from 35 hVISA/vancomycin-intermediate S. aureus (VISA) and 90 vancomycin-susceptible S. aureus isolates. The vancomycin susceptibility of the isolates was determined using an Etest and modified population analysis profile–area under the curve. ML algorithms, namely a decision tree, k-nearest neighbors, random forest, and a support vector machine (SVM), were trained and validated using nested cross-validation to provide unbiased validation results. The area under the curve of the models ranged from 0.67 to 0.79, and the SVM-derived model outperformed those of the other algorithms. The peaks at m/z 1132, 2895, 3176, and 6591 were noted as informative peaks for detecting hVISA/VISA. We demonstrated that hVISA/VISA could be detected by analyzing MALDI-TOF mass spectra using ML. Moreover, the results are particularly robust due to a strict validation method. The ML models in this study can provide rapid and accurate reports regarding hVISA/VISA and thus guide the correct administration of antibiotics in treatment of S. aureus infection.

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Section: Discussionmentioning

confidence: 99%

“…Genetic alterations in TCRS genes are strongly associated with S. aureus glycopeptide-resistance [ 8 , 50 ]. Reduced bacterial susceptibility to vancomycin is related to point mutations at cell wall synthesis genes [ 50 ], as well as antimicrobial resistance genes [ 6 , 8 ]. Point mutations at Mu50 (VISA) strain at vraS (I5N), msrR (E146K), graR (N197S), rpoB (H481Y), and fdh2 (A297V) genes, and at Mu3 (heterogeneous VISA, hVISA) strain at vraS (I5N) and msrR (E146K) genes could lead to an intermediate-resistance phenotype [ 6 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…Other authors suggested that this point mutation leads to the constitutive activation of vraSR operon leading to an up-regulation of cell wall synthesis genes [ 6 ]. Further studies are necessary to clarify the role of such point mutations in the VISA phenotype since previous studies also showed some of these SNVs, including L218P and Y237H at tcaA and V360I at tcaB genes on vancomycin-susceptible isolates [ 50 , 51 ] (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

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Genome Sequence of a Highly Virulent pvl-positive Vancomycin intermediate- resistant Staphylococcus aureus Sequence Type 30

Chamon

Marques

Timenetsky

et al. 2020

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Background: Staphylococcus aureus isolates expressing the Panton-Valentine Leukocidin (PVL) have been related to a wide range of diseases. Recently, pvl-positive community-associated methicillin-resistant S. aureus belonging to USA1100 (ST30/CC30/SCCmec IV) lineage has emerged in Brazilian hospitals. Objective: The aim of this work was to sequence the genome of a pvl-positive USA1100 Vancomycin- Intermediate-Resistant S. aureus (VISA) isolate from Rio de Janeiro, Brazil. Methods: The 13420 genome was sequenced using the HiSeq 2500 platform. The draft genome, plasmids annotation, and genome analysis were performed using RAST. Comparison of the relative pvl gene expression of six S. aureus isolates was performed by qRT-PCR. Results: The isolate presented the ϕPVL phage codifying for the H2b PVL protein isoform, and another prophage carrying a PVL variant named lukF and lukS-PV.2. The 13420 genome presented a high number of virulence determinants, such as genes codifying for serine-protease proteins, enterotoxins (egc), the immune evasion cluster (IEC), adhesion proteins, spermine/spermidine acetyltransferase gene (blt), superantigen-like proteins, as well as the ica operon. Point mutations at vraS, tcaA, and tcaB genes were detected. Moreover, the PVL mRNA relative expression of the 13420 isolate was five times higher than mRNA PVL levels of the USA300/ST8 reference strain. Conclusion: We described for the first time the genome sequence of a VISA isolate harboring two pvl-associated genes and other virulence factors that may improve the USA1100/ST30 lineage fitness and impact its pathogenicity and spreading at Brazilian hospitals.

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Novel single-nucleotide variations associated with vancomycin resistance in vancomycin-intermediate <em>Staphylococcus aureus</em>

Cited by 15 publications

References 47 publications

Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India

Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India

Rapid Detection of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Based on Matrix-Assisted Laser Desorption Ionization Time-of-Flight: Using a Machine Learning Approach and Unbiased Validation

Genome Sequence of a Highly Virulent pvl-positive Vancomycin intermediate- resistant Staphylococcus aureus Sequence Type 30

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