Abstract
Staphylococcus aureus (S. aureus) infections are notoriously complicated by the ability of the organism to grow in biofilms and are difficult to eradicate with antimicrobial therapy. The purpose of the current study was to clarify the influence of sub-inhibitory concentrations (sub-MICs) of daptomycin and tigecycline antibiotics on biofilm adhesion factors and exoproteins expressions by S. aureus clinical isolates. Six clinical isolates representing positive biofilm S. aureus clones (3 methicillin-sensitive S. aureus (MSSA) and 3 methicillin-resistant S. aureus (MRSA)) were grown with sub-MICs (0.5 MIC) of two antibiotics (daptomycin and tigecycline) for 12 h of incubation. RNA extracted from culture pellets was used via relative quantitative real-time-PCR (qRT-PCR) to determine expression of specific adhesion (fnbA, fnbB, clfA, clfB, fib, ebps, cna, eno) and biofilm (icaADBC) genes. To examine the effect of sub-MIC of these antibiotics on the expression of extracellular proteins, samples from the culture supernatants of six isolates were collected after 12 h of treatment with or without tigecycline in order to profile protein production via 2D gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis (2D gel-SDS-PAGE). Sub-MIC treatment of all clinical MRSA and MSSA strains with daptomycin or tigecycline dramatically induced or suppressed fnbA, fnbB, clfA, clfB, fib, ebps, cna, eno, and icaADBC gene expression. Furthermore, sub-MIC use of tigecycline significantly reduced the total number of separated protein spots across all the isolates, as well as decreasing production of certain individual proteins. Collectively, this study showed very different responses in terms of both gene expression and protein secretion across the various isolates. In addition, our results suggest that sub-MIC usage of daptomycin and tigecycline could signal virulence induction by S. aureus via the regulation of biofilm adhesion factor genes and exoproteins. If translating findings to the clinical treatment of S. aureus, the therapeutic regimen should be adapted depending on antibiotic, the virulence factor and strain type.
Highlights
Staphylococcus aureus (S. aureus) is a major problem in many clinical situations, and antibiotic-resistant forms are classified as a “high priority” pathogen by the World HealthOrganization (WHO) [1]
All isolates assessed were found to be susceptible to daptomycin and tigecycline according to Clinical and Laboratory Standards Institute (CLSI), [20] break points (Table 4)
Different responses in terms of both gene expression and protein secretion were found across all isolates in the present study, taking into account the upand down-modulation of the expression of MSCRAMMs, icaA, icaD, icaB, and icaC genes, may be explained by the different transcription changes that occur in the presence of each antibiotic at low concentration
Summary
Staphylococcus aureus (S. aureus) is a major problem in many clinical situations, and antibiotic-resistant forms are classified as a “high priority” pathogen by the World HealthOrganization (WHO) [1]. Current strategies for treating S. aureus infections reduce its virulence rather than directly killing it [5]. Whether sub-inhibitory antibiotics can effectively reduce the rate of S. aureus resistance is still controversial [6]. A similar study conducted by Stevens et al [10] found both clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes in S. aureus. Their results suggest that protein-synthesis inhibition is an important consideration when selecting antimicrobial agents to treat infections caused by toxin-producing Gram-positive pathogens and that enhanced toxin production contributes to worse outcomes
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