Abstract
Capsule polysaccharide is a major virulence factor for a wide range of bacterial pathogens, including Streptococcus pneumoniae. The biosynthesis of Wzy-dependent capsules in both Gram-negative and –positive bacteria is regulated by a system involving a protein tyrosine phosphatase (PTP) and a protein tyrosine kinase. However, how the system functions is still controversial. In Streptococcus pneumoniae, a major human pathogen, the system is present in all but 2 of the 93 serotypes found to date. In order to study this regulation further, we performed a screen to find inhibitors of the phosphatase, CpsB. This led to the observation that a recently discovered marine sponge metabolite, fascioquinol E, inhibited CpsB phosphatase activity both in vitro and in vivo at concentrations that did not affect the growth of the bacteria. This inhibition resulted in decreased capsule synthesis in D39 and Type 1 S. pneumoniae. Furthermore, concentrations of Fascioquinol E that inhibited capsule also lead to increased attachment of pneumococci to a macrophage cell line, suggesting that this compound would inhibit the virulence of the pathogen. Interestingly, this compound also inhibited the phosphatase activity of the structurally unrelated Gram-negative PTP, Wzb, which belongs to separate family of protein tyrosine phosphatases. Furthermore, incubation with Klebsiella pneumoniae, which contains a homologous phosphatase, resulted in decreased capsule synthesis. Taken together, these data provide evidence that PTPs are critical for Wzy-dependent capsule production across a spectrum of bacteria, and as such represents a valuable new molecular target for the development of anti-virulence antibacterials.
Highlights
Capsule polysaccharides (CPS) are fundamental virulence factors for a wide range of Gram-negative (e.g. Klebsiella pneumoniae and Escherichia coli) and Gram-positive (e.g. Streptococcus pneumoniae and Staphylococcus aureus) bacterial pathogens
Its regulation is similar across both genera, with a protein tyrosine phosphatase (PTP) and a protein-tyrosine kinase (PTK) controlling synthesis of one major class of CPS
We are interested in the regulation of its synthesis in the major human pathogen, Streptococcus pneumoniae
Summary
Capsule polysaccharides (CPS) are fundamental virulence factors for a wide range of Gram-negative (e.g. Klebsiella pneumoniae and Escherichia coli) and Gram-positive (e.g. Streptococcus pneumoniae and Staphylococcus aureus) bacterial pathogens. Streptococcus pneumoniae, commonly known as the pneumococcus, is a major human pathogen responsible for significant morbidity and mortality worldwide [16]. Both management and prevention of pneumococcal disease is becoming ever more difficult due to elevated rates of antibiotic resistance and increasing evidence of serotype switching and vaccine evasion to the current vaccine [17]. The CPS is widely accepted as the major virulence factor of the pneumococcus, due to its ability to act as an anti-phagocytic factor [19], and is the target of currently used vaccines. Unencapsulated pneumococci are essentially avirulent and are unable to cause invasive pneumococcal disease, with mutations in CPS synthesis causing significant loss of virulence in animal models [6,21,22]
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