5,5′‐Methylenedisalicylic Acid (MDSA) Modulates SarA/MgrA Phosphorylation by Targeting Ser/Thr Phosphatase Stp1

Abstract

SarA (staphylococcal accessory protein A), MgrA (MarR family of global transcriptional regulator A), and SarZ (a paralogue of SarA) play critical roles in modulating the virulence, drug resistance and autolysis of Staphylococcus aureus. Recently, eukaryotic-like Ser/Thr kinase/phosphatases (Stk1/Stp1) were found to modulate phosphorylation of these transcriptional regulators as well as staphylococcal virulence. Importantly, an stp1-deficient strain showed significant virulence reduction in mice, indicative of Stp1 as a potential drug target. Here, we report that MDSA, an inhibitor of MgrA, enhances phosphorylation of SarA/MgrA by inhibiting Stp1 in S. aureus. MDSA is a more-potent inhibitor (IC50 =9.68 ± 0.52 μM) of Stp1 than commonly used phosphatase inhibitors. We anticipate that MDSA could be a lead compound to develop new approaches for reducing staph virulence by targeting Stp1.

Identification and Biochemical Characterization of a Novel Protein Phosphatase 2C-Like Ser/Thr Phosphatase in Escherichia coli

“…PphC activity was also unaffected by sodium orthovanadate, a known tyrosine phosphatase inhibitor. Aurin tricarboxylic acid and 5,5= methylene disalycilic acid, which were previously reported to inhibit Staphylococcus aureus Stp1 (35,36), had little effect on PphC phosphatase activity. Similarly, sanguinarine chloride, an inhibitor of human PP2C␣ (37), did not affect phosphatase activity.…”

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“…[267] This strategy was also successful in the eradication of persister cells. [271][272][273] MDSA not only decreased a-toxin expression in in vitro experiments,but also reduced abscess formation in am urine abscess model. [269,270] Thus,i ti sa ni ntriguing antivirulence target.…”

“…5,5'-Methylenedisalicylic acid (MDSA) was found to disrupt the DNA-MgrA interaction by both directly blocking MgrA and enhancing MgrA phosphorylation. [271][272][273] MDSA not only decreased a-toxin expression in in vitro experiments,but also reduced abscess formation in am urine abscess model. [273] Additionally,anatural product inspired a-methylene-gbutyrolactone downregulated expression of the virulence factor by binding to transcriptional regulators,i ncluding MgrA and SarA (Figure 18).…”

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“…[268] Ein weiterer zentraler Mechanismus ist die transkriptionelle Regulation, bei der direkt die Expression der Virulenzassoziierten Gene beeinflusst wird. [271][272][273] MDSA verringerte hierbei nicht nur die a-Toxinproduktion in vitro,s ondern reduzierte ebenfalls die Abszessgrçße im Mausmodell. [269,270] Es handelt sich dabei folglich um ein bedeutendes Antivirulenz-Target.…”

“…Es wurde entdeckt, dass die Verbindung 5,5'-Methylendisalicylsäure (5,5'-methylenedisalicylic acid, MDSA) die DNA-MgrA-Interaktion, sowohl durch direktes Blockieren von MgrA als auch die Verstärkung der Phosphorylierung von MgrA, stçrt. [271][272][273] MDSA verringerte hierbei nicht nur die a-Toxinproduktion in vitro,s ondern reduzierte ebenfalls die Abszessgrçße im Mausmodell. [273] Zudem konnte das auf einem Naturstoff basierende a-Methylen-g-butyrolacton die Expression von Virulenzfaktoren verringern, indem es an transkriptionelle Regulatoren, einschließlich MgrA und SarA, band (Abbildung 18).…”