Efficacy of novel antibacterial compounds targeting histidine kinase YycG protein

Abstract

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.

Inactivation of Multiple Bacterial Histidine Kinases by Targeting the ATP-Binding Domain

“…Furthermore, the aminothiazole of 11 and 12 , the urea of 13 , and the aminotriazole of 14 are consistent components of GHL inhibitory compounds, and several also appear in other HK studies ( Supporting Information Figure 26b ). 23 , 27 , 46 , 48 − 51 Evidence of these successes in proteins with similar ATP-binding domains validate the scaffolds identified in our studies and will provide guidance in future inhibitor development.…”

“… 13 In silico screens targeting the ATP-binding domain from a specific HK have led to the identification of molecules that inhibited these proteins in vitro , possessed antibacterial activity, 23 , 24 and in several cases, they showed promise in animal infection models. 25 − 27 Examples of ATP-competitive compounds that more broadly affect HKs have also been reported. Walkmycin C inhibited three purified HKs and repressed pathogenic phenotypes in Streptococcus mutans, ( 28 ) and TEP (3,6-diamino-5-cyano-4-phenylthieno[2,3- b ]pyridine-2-carboxylic acid (4-bromo-phenyl)-amide) deactivated four HK proteins with fifty-percent inhibitory concentrations (IC 50 values) in the low micromolar range.…”

Antibacterial and anti-biofilm activities of thiazolidione derivatives against clinical staphylococcus strains

“…Several derivatives with more effective antibacterial activity were then screened out. 21 , 22 , 23 In this study, 163 clinical strains of S. aureus and S. epidermidis were collected from three tertiary hospitals in eastern China and used to evaluate the anti-bacteria activities of the newly synthesized derivatives of Compound 2 (H2-38, 3-{5-{{3-(4-chlorophenyl)-2-[(4-chlorophenyl)imino]-4-oxothiazolidin-5-ylidene}methyl}furan-2-yl}benzoic acid; H2-39, 4-{5-{{3-(4-chlorophenyl)-2-[(4-chlorophenyl)imino]-4-oxothiazolidin-5-ylidene}methyl}furan-2-yl}benzoic acid; H2-74, 2-{4-{{3-(4-chlorophenyl)-2-[(4-chlorophenyl)imino]-4-oxothiazolidin-5-ylidene}methyl}phenoxy}acetic acid; and H2-81, 4-{5-{{3-(4-fluorophenyl)-2-[(4-phenyl)imino]-4-oxothiazolidin-5-ylidene}methyl}thiophene-2-yl}benzoic acid) against the clinical staphylococcal isolates under planktonic and biofilm growth conditions.…”

Gene Network Analysis of Metallo Beta Lactamase Family Proteins Indicates the Role of Gene Partners in Antibiotic Resistance and Reveals Important Drug Targets

“…YycF and YycG (Cluster 11) have been suggested as potential targets for the development of novel antimicrobial agents and thus are present in two‐component system [bca02020] (Table ). They play an important role in regulatory system for cell wall metabolism and are essential for cell viability [Gotoh et al, ; Liu et al, ]. The remaining functional partners (Table ) in clusters 11 are found to be essential in bacterial cell cycle, translation, RNA binding, metal ion binding that are highly supported with topological properties; however due to inadequate experimental reports the specific role of these proteins in drug resistance are not clear.…”