Discovery of novel Thymol-TPP antibiotics that eradicate MRSA persisters.

The high prevalence of methicillin-resistant Staphylococcus aureus (MRSA) strains and the formation of non-growing, dormant "persisters" subsets help bacteria evade antibiotic treatment and enhance bacterial resistance, which poses a serious threat to human life and health. It is urgent to discover novel antibacterial therapies effective against MRSA persisters. Thymol is a common nutraceutical with weak antibacterial and antitumor activities. A series of Thymol triphenylphosphine (TPP) conjugates (TPP-Thy3) was designed and synthesized. These compounds showed significantly improved inhibitory activity against Gram-positive bacteria compared with Thymol. Among them, Thy3d displayed a low probability of resistance selection and showed excellent biocompatibility. Interestingly, Thy3d elicited a rapid killing effect of MRSA persisters (99.999%) at high concentration. Fluorescence experiments, electron microscopy, molecular dynamics simulation and bilayer experiment confirmed that Thy3d conjugates exerted potent antimicrobial activity by disrupting the integrity of the membrane of bacterial even the persister. Furthermore, Thy3d exhibited considerable efficacy in a mouse model of subcutaneous murine MRSA infection. In summary, TPP-Thy3 conjugates are a series of novel antibacterial agents and could serve as a new therapeutic strategy for combating antibiotic resistance.

Uncovering the anti-biofilm activity of Ilicicolin B against Staphylococcus aureus.

The formation of bacterial biofilms reduces the entry of antibiotics into bacteria and helps bacteria tolerate otherwise lethal concentrations of antimicrobials, leading to antibiotic resistance. Therefore, clearing bacterial biofilm is an effective strategy to tackle drug resistance. Currently, there are no approved antibiotics for inhibiting bacterial biofilm formation. We found that Ilicicolin B had excellent antibacterial activity against MRSA without obvious hemolytic activity. More importantly, Ilicicolin B effectively inhibited the biofilm formation in a concentration-dependent manner by crystal violet colorimetric assay and fluorescence microscopy analysis. Exposure of Staphylococcus aureus to Ilicicolin B for 24 h reduced the protein and polysaccharide components in EPS, suggesting that Ilicicolin B disintegrated the biofilms by dissociating the EPS in a matrix. In addition, Ilicicolin B demonstrated strong antibacterial effects in a murine abscess model of S. aureus. Our findings suggest that Ilicicolin B has the potential to treat S. aureus infection by inhibiting biofilm formation.

2,4-Diacetylphloroglucinol (DAPG) derivatives rapidly eradicate methicillin-resistant staphylococcus aureus without resistance development by disrupting membrane.

Methicillin-resistant Staphylococcus aureus (MRSA) causes severe public health challenges throughout the world, and the multi-drug resistance (MDR) of MRSA to antibiotics necessitates the development of more effective antibiotics. Natural 2,4-diacetylphloroglucinol (DAPG), produced by Pseudomonas, displays moderate inhibitory activity against MRSA. A series of DAPG derivatives was synthesized and evaluated for their antibacterial activities, and some showed excellent activities (MRSA MIC = 0.5-2 µg/mL). Among these derivatives, 7g demonstrated strong antibacterial activity without resistance development over two months. Mechanistic studies suggest that 7g asserted its activity by targeting bacterial cell membranes. In addition, 7g exhibited significant synergistic antibacterial effects with oxacillin both in vitro and in vivo, with a tendency to eradicate MRSA biofilms. 7g is a promising lead for the treatment of MRSA.

Multi-element geochemical mapping in Southern China.

The 76-element Geochemical Mapping (76 GEM) Project was undertaken in southwestern China in 2000 and in southeastern China in 2008. In this project, 5244 composite samples of stream sediment at a density of one composite sample for each 1:50,000-scale map sheet were prepared from sample archives of the China Regional Geochemistry-National Reconnaissance (RGNR) Project, which have been available since 1978. The 76 elements were analyzed by using inductively coupled plasma mass spectrometry (ICP-MS), X-ray fluorescence (XRF), and inductively coupled plasma atomic emission spectroscopy (ICP-AES). In the present study, a new quality-control method known as the visualized standard map method was applied to the results of the 76 GEM project. Mean value and background value, which indicate the average concentration of the 76 elements in southern China, were derived from statistical data. Moreover, geochemical maps were compiled to demonstrate the distribution of the 76 elements in southern China.