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.

Diazido-{(S)-1-phenyl-N,N-bis-[(2-pyrid-yl)meth-yl]ethanamine}-copper(II).

In the title compound, [Cu(N(3))(2)(C(20)H(21)N(3))], the Cu(II) ion is coordinated by the three N atoms of the (S)-1-phenyl-N,N-bis-[(2-pyrid-yl)meth-yl]ethanamine ligand and two N atoms from two azide anions, resulting in a distorted square-pyramidal environment. A weak inter-molecular C-H⋯N hydrogen-bonding inter-action between one pyridine group of the ligand and an azide N atom of an adjacent complex unit gives a one-dimensional chain structure parallel to the c axis.

Acetonitrile-{3-[bis-(2-pyridyl-methyl-κN)amino-κN]propanol-κO}(perchlorato-κO)copper(II) perchlorate.

In the title compound, [Cu(ClO(4))(C(2)H(3)N)(C(15)H(19)N(3)O)]ClO(4), the Cu(II) ion is coordinated by three N atoms and a hydroxyl-O atom of the tetra-dentate ligand, an O atom of a perchlorate ion and an N atom of an acetonitrile ligand giving a tetra-gonally distorted octa-hedral environment around the copper(II) atom. There is an offset inter-complex face-to-face π-π inter-action [centroid-centroid distance = 3.718 (2) Å] involving one of the pyridine rings of the ligand as well as an intra-complex O-H⋯O hydrogen-bonding inter-action between the coordinated hydroxyl group of the ligand and the perchlorate counter-ion.

Monomeric, trimeric, and tetrameric transition metal complexes (Mn, Fe, Co) containing N,N-bis(2-pyridylmethyl)-2-aminoethanol/-ate: preparation, crystal structure, molecular magnetism and oxidation catalysis.

The reaction of N,N-bis(2-pyridylmethyl)-2-aminoethanol (bpaeOH), NaSCN/NaN(3), and metal (M) ions [M = Mn(II), Fe(II/III), Co(II)] in MeOH, leads to the isolation of a series of monomeric, trimeric, and tetrameric metal complexes, namely [Mn(bpaeOH)(NCS)(2)] (1), [Mn(bpaeO)(N(3))(2)] (2), [Fe(bpaeOH)(NCS)(2)] (3), [Fe(4)(bpaeO)(2)(CH(3)O)(2)(N(3))(8)] (4), [Co(bpaeOH)(NCS)(2)] (5), and [Co(3)(bpaeO)(2)(NO(3))(N(3))(4)](NO(3)) (6). These compounds have been investigated by single crystal X-ray diffractometry and magnetochemistry. In complex 1 the Mn(II) is bonded to one bpaeOH and two thiocyanate ions, while in complex 2 it is coordinated to a deprotonated bpaeO(-) and two azide ions. The oxidation states of manganese ions are 2+ for 1 and 3+ for 2, respectively, indicating that the different oxidation states depend on the type of binding anions. The structures of monomeric iron(II) and cobalt(II) complexes 3 and 5 with two thiocyanate ions are isomorphous to that of 1. Compounds 1, 2, 3, and 5 exhibit high-spin states in the temperature range 5 to 300 K. 4 contains two different iron(III) ions in an asymmetric unit, one is coordinated to a deprotonated bpaeO(-), an azide ion, and a methoxy group, and the other is bonded to three azide ions and two oxygens from bpaeO(-) and a methoxy group. Two independent iron(III) ions in 4 form a tetranuclear complex by symmetry. 4 displays both ferromagnetic and antiferromagnetic couplings (J = 9.8 and -14.3 cm(-1)) between the iron(III) ions. 6 is a mixed-valence trinuclear cobalt complex, which is formulated as Co(III)(S = 0)-Co(II)(S = 3/2)-Co(III)(S = 0). The effective magnetic moment at room temperature corresponds to the high-spin cobalt(II) ion (∼4.27 µ(B)). Interestingly, 6 showed efficient catalytic activities toward various olefins and alcohols with modest to excellent yields, and it has been proposed that a high-valent Co(V)-oxo species might be responsible for oxygen atom transfer in the olefin epoxidation and alcohol oxidation reactions.

Synthesis and characterization of enantiopure copper(II) complexes using chiral bidentate ligands.

Chiral copper(ii) complexes of the types [Cu(II)(R/S-ppme)(3)](ClO(4))(2) and [Cu(II)(R/S-ppme)(2)(SO(4))] have been synthesized by reactions of Cu(ClO(4))(2).6H(2)O and CuSO(4).5H(2)O with R/S-ppme in methanol under aerobic conditions (R/S-ppme = (R/S)-(+/-)-1-phenyl-N-(pyridine-2-ylmethylene)ethanamine). All complexes were isolated and characterized by X-ray crystallography and circular dichroism (CD): (Lambda)-[Cu(II)(R-ppme)(3)](ClO(4))(2) (1), (Delta)-[Cu(S-ppme)(3)](ClO(4))(2).H(2)O (2), (Delta)-[Cu(II)(R-ppme)(2)(SO(4))].4CH(3)OH (3), and (Lambda)-[Cu(II)(S-ppme)(2)(SO(4))].4CH(3)OH (4). 1 and 2 with ClO(4)(-) anions are formed as tris(R/S-ppme) copper(ii) complexes, while 3 and 4 with SO(4)(2-) are formed as bis(R/S-ppme) copper(ii) complexes. The structures of 1 with R-ppmes and 4 with S-ppmes show the same absolute configurations (Lambda). In contrast, 2 with S-ppmes and 3 with R-ppmes exhibit Delta configurations. In the electron paramagnetic resonance (EPR) spectra of 1 and 3, both compounds demonstrate z-axis elongated structures. The CD spectra of 1 and 2 show Cotton effects in an enantiomeric pattern; those of 3 and 4 also display the same effects.

A zigzag tetranuclear iron(III) complex, [Fe4(bpaeO)2(CH3O)2(N3)8] coexisting both ferromagnetic and antiferromagnetic couplings (bpaeOH = N,N-bis(2-pyridylmethyl)-2-aminoethanol).

A zigzag tetranuclear [Fe(4)(bpaeO)(2)(CH(3)O)(2)(N(3))(8)] possesses two different high-spin ferric sites and both ferromagnetic and antiferromagnetic interactions exist within the iron(III) ions.

trans-{1,8-Bis[(S)-1-phenyl-eth-yl]-1,3,6,8,10,13-hexa-aza-cyclo-tetra-deca-ne}bis(thio-cyanato--κN)copper(II).

In the title thio-cyanate-coordinated aza-macrocyclic copper(II) complex, [Cu(NCS)(2)(C(24)H(38)N(6))], the Cu(II) atom is coordinated by the four secondary N atoms of the aza-macrocyclic ligand and by the two N atoms of the thio-cyanate ions in a tetra-gonally distorted octa-hedral geometry. The average equatorial Cu-N bond length is shorter than the average axial Cu-N bond length [2.010 (2) and 2.528 (4) Å, respectively]. An N-H⋯N hydrogen-bonding inter-action between the secondary amine N atom and the adjacent thio-cyanate ion leads to a polymeric chain along the a axis.

{3-[Bis(2-pyridyl-methyl-κN)amino-κN]propanol}bis-(nitrato-κO)copper(II).

In the title compound, [Cu(NO(3))(2)(C(15)H(19)N(3)O)], the Cu(II) ion is coordinated by the N atoms of the tetra-dentate 3-[bis-(2-pyridyl-meth-yl)amino]-propanol ligand and two O atoms from two monodentate nitrate anions, resulting in a distorted square-pyramidal environment. An inter-molecular O-H⋯O hydrogen-bonding inter-action between the free hy-droxy group of the ligand and a nitrate O atom of an adjacent complex unit, gives a chain structure which extends across the (101) planes.