Anti-bacterial and Anti-biofilm Evaluation of Thiazolopyrimidinone Derivatives Targeting the Histidine Kinase YycG Protein of Staphylococcus epidermidis

Abstract

Staphylococcus epidermidis is one of the most important opportunistic pathogens in nosocomial infections. The main pathogenicity associated with S. epidermidis involves the formation of biofilms on implanted medical devices, biofilms dramatically decrease the efficacy of conventional antibiotics and the host immune system. This emphasizes the urgent need for designing novel anti-staphylococcal biofilm agents. Based on the findings that compound 5, targeting the histidine kinase domain of S. epidermidis YycG, possessed bactericidal activity against staphylococci, 39 derivatives of compound 5 with intact thiazolopyrimidinone core structures were newly designed, 7 derivatives were further screened to explore their anti-bacterial and anti-biofilm activities. The seven derivatives strongly inhibited the growth of S. epidermidis and Staphylococcus aureus in the minimal inhibitory concentration range of 1.56–6.25 μM. All the derivatives reduced the proportion of viable cells in mature biofilms. They all displayed low cytotoxicity on mammalian cells and were not hemolytic to human erythrocytes. The biofilm inhibition activities of four derivatives (H5-32, H5-33, H5-34, and H5-35) were further investigated under shearing forces, they all led to significant decreases in the biofilm formation of S. epidermidis. These results were suggestive that the seven derivatives of compound 5 have the potential to be developed into agents for eradicating biofilm-associated infections.

Monoclonal Antibodies Specific to the Extracellular Domain of Histidine Kinase YycG of Staphylococcus epidermidis Inhibit Biofilm Formation

“…YycG/YycF TCS regulates S. epidermidis biofilm formation ( Xu et al, 2017 ). Because inhibitors targeting the cytoplasmic HATPase_c domain of YycG exhibit anti-biofilm activity ( Qin et al, 2006 ; Huang et al, 2012 ; Liu et al, 2014 ; Lv et al, 2017 ), we generated mAbs against the extracellular domain of YycG (YycG ex , aa 34–184) of S. epidermidis RP62A, and from nine hybridoma lines, we selected for further investigation the two mAbs (2F3 and 1H1) that exhibited the highest affinity for the protein.…”

“…The YycG/YycF TCS is essential for bacterial growth and plays a major role in biofilm formation ( Fukuchi et al, 2000 ; Howell et al, 2003 ; Mohedano et al, 2005 ; Ahn and Burne, 2007 ; Bisicchia et al, 2007 ). YycG histidine kinase is a transmembrane protein, and we have shown that inhibitors that target the cytoplasmic HATPase_c domain of S. epidermidis exhibit bactericidal and biofilm-killing activities ( Qin et al, 2006 ; Huang et al, 2012 ; Liu et al, 2014 ; Lv et al, 2017 ). Previous studies have found that the extracellular domain of the protein (YycG ex domain) adopts a PAS fold predicted as a sensor of YycG by sensing environmental signals such as oxygen, light, redox potential, or the presence of specific ligands ( Taylor and Zhulin, 1999 ; Santelli et al, 2007 ; Chang et al, 2010 ; Shah et al, 2013 ; Kim et al, 2016 ), but little is known of the nature of the signals and factors sensed by YycG.…”

“…The YycG histidine kinase of S. epidermidis prototypically contains two transmembrane sections, an extracytoplasmic loop (YycG ex domain), cytoplasmic HAMP and Per-Arnt-Sim (PAS) domains, and a catalytic core of HisKA and HATPase_c domains ( Ng and Winkler, 2004 ; Dubrac et al, 2008 ). Our previous work demonstrated that inhibitors targeting the HATPase_c domain exhibit not only bactericidal activity but also potent activity against staphylococcal biofilms ( Qin et al, 2006 ; Huang et al, 2012 ; Liu et al, 2014 ; Lv et al, 2017 ). Thus, we hypothesized that monoclonal antibodies (mAbs) against the YycG ex domain would block the signal transduction and thereby influence the phenotypic properties of S. epidermidis RP62A.…”

Selection and Identification of Novel Antibacterial Agents against Planktonic Growth and Biofilm Formation of Enterococcus faecalis

“…epidermidis and S. aureus. ,, In this study, the highly conserved sequence of the YycFG TCS in these bacterial species supported the designing of molecules targeting its HK for the development of novel antibacterial drugs against E. faecalis.…”

Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target

“…(20) Also, it has been shown in some patients with PBC that there is depletion of the nonpathogenic bacteria useful to the body to the benefit of pathogenic and opportunistic bacteria such as Veillonella and Streptococcus. (21) Recently, some therapies referring to fecal microbiota transplantation (FMT) have emerged. FMT consists of introducing beneficial commensal bacteria into the gut of patients with diseases whose gut dysbiosis plays a role in the initiation and progression.…”