Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes

Subramanian, Devika; Natarajan, Jeyakumar

doi:10.1016/j.gene.2015.08.006

Cited by 15 publications

(11 citation statements)

References 74 publications

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“…Interestingly, cleavage of UACAU sites can be detected in a WT strain without overexpression of the toxin or deletion of the antitoxin [ 55 ] which suggests that MazF might play a regulatory role for certain transcripts even under non-stress conditions. Because of the abundance of UACAU sites in the pathogenicity factor sraP gene [ 66 ] and clustering in functional association networks [ 70 ], an involvement of mazEF in pathogenicity has been proposed. However, since the association of mazEF with sigB is highly conserved also in other Staphylococcus species and since mazEF is also functional in the non-pathogenic S. equorum [ 36 ], it remains to be worked out to what extent pathogenesis and cell physiology are regulated by mazEF .…”

Section: Type II Ta Systemsmentioning

confidence: 99%

Toxin-Antitoxin Systems of Staphylococcus aureus

Schuster

Bertram

2016

Toxins

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Toxin-antitoxin (TA) systems are small genetic elements found in the majority of prokaryotes. They encode toxin proteins that interfere with vital cellular functions and are counteracted by antitoxins. Dependent on the chemical nature of the antitoxins (protein or RNA) and how they control the activity of the toxin, TA systems are currently divided into six different types. Genes comprising the TA types I, II and III have been identified in Staphylococcus aureus. MazF, the toxin of the mazEF locus is a sequence-specific RNase that cleaves a number of transcripts, including those encoding pathogenicity factors. Two yefM-yoeB paralogs represent two independent, but auto-regulated TA systems that give rise to ribosome-dependent RNases. In addition, omega/epsilon/zeta constitutes a tripartite TA system that supposedly plays a role in the stabilization of resistance factors. The SprA1/SprA1AS and SprF1/SprG1 systems are post-transcriptionally regulated by RNA antitoxins and encode small membrane damaging proteins. TA systems controlled by interaction between toxin protein and antitoxin RNA have been identified in S. aureus in silico, but not yet experimentally proven. A closer inspection of possible links between TA systems and S. aureus pathophysiology will reveal, if these genetic loci may represent druggable targets. The modification of a staphylococcal TA toxin to a cyclopeptide antibiotic highlights the potential of TA systems as rather untapped sources of drug discovery.

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Section: Type II Ta Systemsmentioning

confidence: 99%

Toxin-Antitoxin Systems of Staphylococcus aureus

Schuster

Bertram

2016

Toxins

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“…Purine metabolism is a necessary part of DNA synthesis and energy production in S. aureus [ 50 ]. Genes involved in purine metabolism are often downregulated after treatment with a drug or plant extract [ 51 , 52 , 53 ]. In addition, one gene associated with pyrimidine synthesis, tdk , was upregulated.…”

Section: Resultsmentioning

confidence: 99%

Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

et al. 2017

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The mechanism of action for a new lead stilbene compound coded SK-03-92 with bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) is unknown. To gain insight into the killing process, transcriptional profiling was performed on SK-03-92 treated vs. untreated S. aureus. Fourteen genes were upregulated and 38 genes downregulated by SK-03-92 treatment. Genes involved in sortase A production, protein metabolism, and transcriptional regulation were upregulated, whereas genes encoding transporters, purine synthesis proteins, and a putative two-component system (SACOL2360 (MW2284) and SACOL2361 (MW2285)) were downregulated by SK-03-92 treatment. Quantitative real-time polymerase chain reaction analyses validated upregulation of srtA and tdk as well as downregulation of the MW2284/MW2285 and purine biosynthesis genes in the drug-treated population. A quantitative real-time polymerase chain reaction analysis of MW2284 and MW2285 mutants compared to wild-type cells demonstrated that the srtA gene was upregulated by both putative two-component regulatory gene mutants compared to the wild-type strain. Using a transcription profiling technique, we have identified several cellular pathways regulated by SK-03-92 treatment, including a putative two-component system that may regulate srtA and other genes that could be tied to the SK-03-92 mechanism of action, biofilm formation, and drug persisters.

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“…8, 17, 19, 23–26 For type II TA modules, the microbial general stress response induces bacterial cellular proteases, such as Lon and ClpXP, that degrade the labile antitoxin portion of the TA protein complex, freeing the more stable toxin protein to exert its effects (Figure 1). 27 Many type II TA toxins are ribonucleases that degrade bacterial mRNA in a sequence-specific or nonspecific fashion, causing the organism to enter a state of bacteriostasis 3, 28–34 This is beneficial to a pathogenic bacterium, particularly during an infection, as growth arrest significantly decreases its metabolic burden, accumulation of DNA damage from reactive oxygen species, as well as minimizing the production of molecular patterns that signal receptors of the host’s immune response.…”

Section: Clinical Importance Of Toxin-antitoxin Modulesmentioning

confidence: 99%

Wake me when it’s over – Bacterial toxin–antitoxin proteins and induced dormancy

Coussens

Daines

2016

Exp Biol Med (Maywood)

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Toxin-antitoxin (TA) systems are encoded by bacteria and archaea to enable an immediate response to environmental stresses, including antibiotics and the host immune response. During normal conditions, the antitoxin components prevent toxins from interfering with metabolism and arresting growth; however, toxin activation enables microbes to remain dormant through unfavorable conditions that might continue over millions of years. Intense investigations have revealed a multitude of mechanisms for both regulation and activation of TA systems, which are abundant in pathogenic microorganisms. This minireview provides an overview of the current knowledge regarding type II TA systems along with their clinical and environmental implications.

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Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes

Cited by 15 publications

References 74 publications

Toxin-Antitoxin Systems of Staphylococcus aureus

Toxin-Antitoxin Systems of Staphylococcus aureus

Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

Wake me when it’s over – Bacterial toxin–antitoxin proteins and induced dormancy

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