Response of Staphylococcus aureus to subinhibitory concentrations of a sequence-selective, DNA minor groove cross-linking pyrrolobenzodiazepine dimer

被引:12
作者
Doyle, Marie [1 ]
Feuerbaum, Eva-Anne [1 ]
Fox, Keith R. [2 ]
Hinds, Jason [3 ]
Thurston, David E. [1 ]
Taylor, Peter W. [1 ]
机构
[1] Univ London, Sch Pharm, London WC1N 1AX, England
[2] Univ Southampton, Sch Biol Sci, Southampton SO16 7PX, Hants, England
[3] St Georges Univ London, Div Cellular & Mol Med, London SW17 0RE, England
基金
英国惠康基金;
关键词
S; aureus; DNA cross-linking; DNA damage response; sequence-selective DNA binding; SIGNAL-TRANSDUCTION; VIRULENCE FACTORS; AGENT SJG-136; SOS RESPONSE; HEAT-SHOCK; CELL-WALL; RESISTANCE; INSIGHTS; GENOME;
D O I
10.1093/jac/dkp325
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Objectives: ELB-21 is a pyrrolo[2,1-c][1,4]benzodiazepine dimer with potent antistaphylococcal activity; it binds covalently to guanine residues on opposing strands of duplex DNA, interfering with regulatory proteins and transcription elongation in a sequence-selective manner. Transcriptional and proteomic alterations induced by exposure of Staphylococcus aureus clinical isolate EMRSA-16 to ELB-21 were determined in order to define more precisely the bactericidal mechanism of the drug. Methods: DNase I footprinting was used to identify high-affinity DNA binding sites. Microarrays and gel electrophoresis were used to assess the ELB-21-induced phenotype. Results: High-affinity interstrand binding sites in which guanine residues were separated by 4 bp, and also some intrastrand cross-linking sites of variable length were identified. Exposure of EMRSA-16 to 0.015 mg/L ELB-21 elicited a 2-fold or greater up-regulation of 168 genes in logarithmic phase and 181 genes in stationary phase; the majority of genes affected were associated with resident prophages phi Sa2 and phi Sa3, pathogenicity island SaPl4 and DNA damage repair. ELB-21 induced a marked increase in the number of viable phage particles in culture supernatants. The expression of only a limited number of genes showed a >50% reduction. Sixteen extracellular and four intracellular proteins were differentially expressed during logarithmic and stationary phases, including RecA, proteins associated with staphylococcal pathogenesis (IsaA, CspA), cell division and wall synthesis. Conclusions: ELB-21 kills S. aureus by forming multiple interstrand and intrastrand DNA cross-links, resulting in induction of the DNA damage response, derepression of resident prophages and modulation of a limited number of genes involved with cell wall synthesis.
引用
收藏
页码:949 / 959
页数:11
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