In Silico Genome-Scale Analysis of Molecular Mechanisms Contributing to the Development of a Persistent Infection with Methicillin-Resistant Staphylococcus aureus (MRSA) ST239

Abstract

The increasing frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) limits the chances for the effective antibacterial therapy of staphylococcal diseases and results in the development of persistent infection such as bacteremia and osteomyelitis. The aim of this study was to identify features of the MRSA_ST239 0943-1505-2016 (SA943) genome that contribute to the formation of both acute and chronic musculoskeletal infections. The analysis was performed using comparative genomics data of the dominant epidemic S. aureus lineages, namely ST1, ST8, ST30, ST36, and ST239. The SA943 genome encodes proteins that provide resistance to the host's immune system, suppress immunological memory, and form biofilms. The molecular mechanisms of adaptation responsible for the development of persistent infection were as follows: amino acid substitution in PBP2 and PBP2a, providing resistance to ceftaroline; loss of a large part of prophage DNA and restoration of the nucleotide sequence of beta-hemolysin, that greatly facilitates the escape of phagocytosed bacteria from the phagosome and formation of biofilms; dysfunction of the AgrA system due to the presence of psm-mec and several amino acid substitutions in the AgrC; partial deletion of the nucleotide sequence in genomic island vSAβ resulting in the loss of two proteases of Spl-operon; and deletion of SD repeats in the SdrE amino acid sequence.

Keywords: MRSAST239; Staphylococcus aureus; adaptation; chronic; features; genome; infection; osteomyelitis; pathogenesis.

Figure 1

Structural features of protein A (SpA) domains (sequence aliment protein A binding domains) in S. aureus NCTC8325 (A) and S. aureus SA943 (B). Note: Letters designate structural domains according to Jo. A. Capp et al. (2014) [46]. Letter R denotes the formed recombinant domain. Dots indicate identical amino acids; domain areas differing in amino acid sequences are marked in bold type. The linker region between domains is boxed in black. Each of the domains consists of 3 helix bundles connected by short linkers; * Amino acid insertion (AQQ) between domains E and D (A) or E and R (B). The part of the D domain involved in the formation of R domain is highlighted in blue; the part of the A domain involved in the formation of the R domain is highlighted in green; the deletion region of D and A domains is shown in yellow. The original amino acid substitution in the R domain is highlighted in black italics; red italics highlight amino acids in the R domain that are specific to domain B and C, but representing substitutions in relation to domains D and A; Amino acids that are specific for the B domain and absent in the fragments of the D and A domains that form the R domain are highlighted in red normal fonts.