Comparative Genomics of Borderline Oxacillin-Resistant Staphylococcus aureus Detected during a Pseudo-outbreak of Methicillin-Resistant S. aureus in a Neonatal Intensive Care Unit

Sawhney, Sanjam S.; Ransom, Eric M.; Wallace, Meghan A.; Reich, Patrick; Dantas, Gautam; Burnham, Carey‐Ann D.

doi:10.1128/mbio.03196-21

Cited by 10 publications

(5 citation statements)

References 67 publications

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“…Notably, the latter represents an improvement of the former with higher statistical power. The ability of BratNextGen to reveal ancestral recombination has been applied in studies related to Streptomyces species [ 79 ], antibiotic-resistant Staphylococcus aureus strains [ 80 ], and differentiated Xylella fastidiosa isolates [ 81 ].…”

Section: Current Bioinformatics Tools For Recombination Analysismentioning

confidence: 99%

Current Methods for Recombination Detection in Bacteria

Shikov

Malovichko

Nizhnikov

et al. 2022

IJMS

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The role of genetic exchanges, i.e., homologous recombination (HR) and horizontal gene transfer (HGT), in bacteria cannot be overestimated for it is a pivotal mechanism leading to their evolution and adaptation, thus, tracking the signs of recombination and HGT events is importance both for fundamental and applied science. To date, dozens of bioinformatics tools for revealing recombination signals are available, however, their pros and cons as well as the spectra of solvable tasks have not yet been systematically reviewed. Moreover, there are two major groups of software. One aims to infer evidence of HR, while the other only deals with horizontal gene transfer (HGT). However, despite seemingly different goals, all the methods use similar algorithmic approaches, and the processes are interconnected in terms of genomic evolution influencing each other. In this review, we propose a classification of novel instruments for both HR and HGT detection based on the genomic consequences of recombination. In this context, we summarize available methodologies paying particular attention to the type of traceable events for which a certain program has been designed.

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Section: Current Bioinformatics Tools For Recombination Analysismentioning

confidence: 99%

Current Methods for Recombination Detection in Bacteria

Shikov

Malovichko

Nizhnikov

et al. 2022

IJMS

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“…While PBP2a has historically been considered the main driver of MRSA, the recent finding that high-level S. aureus β-lactam resistance occurs in strains not capable of producing PBP2a has led to investigation of non-canonical pathway(s) of MRSA development as well as fundamental questions regarding the clinical diagnostic practices that rely on detection of mecA , the gene encoding PBP2a, as a MRSA determinant [ 37 ]. Recent studies have revealed that development of PBP2a-independent MRSA is associated with PBP4 production in community-acquired MRSA isolates and/or overproduction of a PBP4 variant within the hospital-acquired strain COL background.…”

Section: Discussionmentioning

confidence: 99%

Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors

et al. 2022

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Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare concern. Such resistance has historically been attributed to the acquisition of mecA (or mecC), which encodes an alternative penicillin binding protein, PBP2a, with low β-lactam affinity. However, recent studies have indicated that penicillin binding protein 4 (PBP4) is also a critical determinant of S. aureus methicillin resistance, particularly among community-acquired MRSA strains. Thus, PBP4 has been considered an intriguing therapeutic target as corresponding inhibitors may restore MRSA β-lactam susceptibility. In addition to its role in antibiotic resistance, PBP4 has also recently been shown to be required for S. aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion and colonization, providing the organism with a niche for re-occurring bone infection. From these perspectives, the development of PBP4 inhibitors may have tremendous impact as agents that both reverse methicillin resistance and inhibit the organism’s ability to cause chronic osteomyelitis. Accordingly, using a whole-cell high-throughput screen of a 30,000-member small molecule chemical library and secondary assays we identified putative S. aureus PBP4 inhibitors. Quantitative reverse transcriptase mediated PCR and PBP4 binding assays revealed that hits could be further distinguished as compounds that reduce PBP4 expression versus compounds that are likely to affect the protein’s function. We also showed that 6.25 µM (2.5 µg/mL) of the lead candidate, 9314848, reverses the organism’s PBP4-dependent MRSA phenotype and inhibits its ability to traverse Microfluidic-Silicon Membrane-Canalicular Arrays (µSiM-CA) that model the OLCN orifice. Collectively, these molecules may represent promising potential as PBP4-inhibitors that can be further developed as adjuvants for the treatment of MRSA infections and/or osteomyelitis prophylactics.

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“…Genomic DNA was isolated from cell-suspensions and sequenced as previously described 23 , 63 . Briefly, DNA was quantified with Quant-iT PicoGreen dsDNA assay (Thermo Fisher Scientific, Waltham, MA, USA), with 0.5 ng used as input for Illumina Nextera XT library preparation (Illumina, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…WGS has enabled comparative genomics studies that have provided foundational knowledge of S. pseudintermedius populations and pathologies 20 , 21 . Similar to S. aureus , S. pseudintermedius has an open pangenome; most accessory genes are lineage- or strain-specific 20 – 23 , and antibiotic resistance gene (ARG) content and virulence factor repertoires vary by multilocus sequence type (MLST) 20 , 24 . Additional studies have characterized S. pseudintermedius genome content by geographic isolation 21 , host-species for clinical isolates 22 , niche-type for veterinary isolates 20 , 25 , and mecA presence 26 .…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and commensal Staphylococcus pseudintermedius genomes reveal niche adaptation through parallel selection of defense mechanisms

Sawhney,

Vargas,

Wallace

et al. 2023

Nat Commun

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Staphylococcus pseudintermedius is historically understood as a prevalent commensal and pathogen of dogs, though modern clinical diagnostics reveal an expanded host-range that includes humans. It remains unclear whether differentiation across S. pseudintermedius populations is driven primarily by niche-type or host-species. We sequenced 501 diagnostic and commensal isolates from a hospital, veterinary diagnostic laboratory, and within households in the American Midwest, and performed a comparative genomics investigation contrasting human diagnostic, animal diagnostic, human colonizing, pet colonizing, and household-surface S. pseudintermedius isolates. Though indistinguishable by core and accessory gene architecture, diagnostic isolates harbor more encoded and phenotypic resistance, whereas colonizing and surface isolates harbor similar CRISPR defense systems likely reflective of common household phage exposures. Furthermore, household isolates that persist through anti-staphylococcal decolonization report elevated rates of base-changing mutations in – and parallel evolution of – defense genes, as well as reductions in oxacillin and trimethoprim-sulfamethoxazole susceptibility. Together we report parallel niche-specific bolstering of S. pseudintermedius defense mechanisms through gene acquisition or mutation.

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Comparative Genomics of Borderline Oxacillin-Resistant Staphylococcus aureus Detected during a Pseudo-outbreak of Methicillin-Resistant S. aureus in a Neonatal Intensive Care Unit

Cited by 10 publications

References 67 publications

Current Methods for Recombination Detection in Bacteria

Current Methods for Recombination Detection in Bacteria

Identification of Staphylococcus aureus Penicillin Binding Protein 4 (PBP4) Inhibitors

Diagnostic and commensal Staphylococcus pseudintermedius genomes reveal niche adaptation through parallel selection of defense mechanisms

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