Treating staphylococcal biofilm-associated infections is challenging. Based on the findings that compound 2 targeting the HK domain of Staphylococcus epidermidis YycG has bactericidal and antibiofilm activities against staphylococci, six newly synthesized derivatives were evaluated for their antibacterial activities. The six derivatives of compound 2 inhibited autophosphorylation of recombinant YycG′ and the IC50 values ranged from 24.2 to 71.2 μM. The derivatives displayed bactericidal activity against planktonic S. epidermidis or Staphylococcus aureus strains in the MIC range of 1.5–3.1 μM. All the derivatives had antibiofilm activities against the 6- and 24-h biofilms of S. epidermidis. Compared to the prototype compound 2, they had less cytotoxicity for Vero cells and less hemolytic activity for human erythrocytes. The derivatives showed antibacterial activities against clinical methicillin-resistant staphylococcal isolates. The structural modification of YycG inhibitors will assist the discovery of novel agents to eliminate biofilm infections and multidrug-resistant staphylococcal infections.Electronic supplementary materialThe online version of this article (doi:10.1007/s00253-014-5685-8) contains supplementary material, which is available to authorized users.

Background: Staphylococcus epidermidis senses and responds to oxidative stress through an unknown mechanism. Results: The paper describes AbfR, the first oxidation sensor of S. epidermidis. Conclusion: AbfR plays key roles in oxidative stress responses, bacterial aggregation, and biofilm formation in S. epidermidis. Significance: Oxidative stress signals S. epidermidis to modulate key virulence properties through AbfR.

e SrrAB expression in Staphylococcus epidermidis strain 1457 (SE1457) was upregulated during a shift from oxic to microaerobic conditions. An srrA deletion (⌬srrA) mutant was constructed for studying the regulatory function of SrrAB. The deletion resulted in retarded growth and abolished biofilm formation both in vitro and in vivo and under both oxic and microaerobic conditions. Associated with the reduced biofilm formation, the ⌬srrA mutant produced much less polysaccharide intercellular adhesion (PIA) and showed decreased initial adherence capacity. Microarray analysis showed that the srrA mutation affected transcription of 230 genes under microaerobic conditions, and 51 genes under oxic conditions. Quantitative real-time PCR confirmed this observation and showed downregulation of genes involved in maintaining the electron transport chain by supporting cytochrome and quinol-oxidase assembly (e.g., qoxB and ctaA) and in anaerobic metabolism (e.g., pflBA and nrdD). In the ⌬srrA mutant, the expression of the biofilm formation-related gene icaR was upregulated under oxic conditions and downregulated under microaerobic conditions, whereas icaA was downregulated under both conditions. An electrophoretic mobility shift assay further revealed that phosphorylated SrrA bound to the promoter regions of icaR, icaA, qoxB, and pflBA, as well as its own promoter region. These findings demonstrate that in S. epidermidis SrrAB is an autoregulator and regulates biofilm formation in an ica-dependent manner. Under oxic conditions, SrrAB modulates electron transport chain activity by positively regulating qoxBACD transcription. Under microaerobic conditions, it regulates fermentation processes and DNA synthesis by modulating the expression of both the pfl operon and nrdDG. Staphylococcus epidermidis is an opportunistic pathogen, seldom excreting virulence factors and less aggressive in comparison to Staphylococcus aureus but capable of forming a multilayered biofilm on implanted medical devices, such as vascular catheters, prosthetic joints, artificial heart valves, etc. (1, 2). The bacteria within the biofilm are protected against killing by antibiotics and the host immune system, which contributes to increasing resistance to antimicrobial drugs and persistent infections (3-5). Biofilm-related infections persist until the biomedical implant is removed, resulting in extra trauma and cost to the patients.Biofilm formation is a complicated process in staphylococci, being regulated by multiple regulatory factors, including Agr P2/ P3, SarA, SigB, and two-component signal transduction systems (TCSs) (6-10). TCSs serve as a basic stimulus-response coupling mechanism by which bacteria adapt the environmental changes and consequently play a key role in pathogenesis (11-13). Our previous study revealed that the TCSs LytSR, SaeRS, and ArlRS are involved in S. epidermidis biofilm formation (14-16), whereas the role of the SrrAB (staphylococcal respiratory response) remained unclear.The SrrAB shares considerable homology with ResDE of Bacill...

Both Staphylococcus aureus and Staphylococcus epidermidis can form biofilms on natural surfaces or abiotic surfaces, such as medical implants, resulting in biofilm-associated diseases that are refractory to antibiotic treatment. We previously reported a promising antibacterial compound (Compound 2) and its derivatives with bactericidal and anti-biofilm activities against both S. epidermidis and S. aureus. We have further evaluated the antibacterial activities of four Compound 2 derivatives (H2-38, H2-39, H2-74 and H2-81) against 163 clinical strains of S. epidermidis and S. aureus, including methicillin-susceptible and methicillin-resistant strains, as well as biofilm-forming and non-biofilm-forming strains. The four derivatives inhibited the planktonic growth of all of the clinical staphylococcal isolates, including methicillin-resistant S. aureus and methicillin-resistant S. epidermidis and displayed bactericidal activities against both immature (6 h) and mature (24 h) biofilms formed by the strong biofilm-forming strains. The derivatives, which all target YycG, will help us to develop new antimicrobial agents against multidrug-resistant staphylococci infections and biofilm-associated diseases.