Author: Duan, Xuemin ; Bu, Simeng ; Xiong, Yanshi ; Jiang, Guangbin ; Liu, Jinyao ; Wang, Jintao ; Liao, Xiangwen ; Shen, Jihong ; Jiang, Guijuan ; Lin, Xiaoli

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)₂(BTPIP)](ClO₄)₂ (Ru(II)-1), [Ru(bpy)₂(ETPIP)](ClO₄)₂ (Ru(II)-2) and [Ru(bpy)₂(CAPIP)](ClO₄)₂ (Ru(II)-3) (N-N = bpy = 2,2'-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.

01 Nov 2015·Medical MycologyQ3 · MEDICINE

In vitroantifungal synergy between amphiphilic aminoglycoside K20 and azoles againstCandida species and Cryptococcus neoformans

Q3 · MEDICINE

Article

Author: Sorensen, Kevin N ; Grilley, Michelle ; Shrestha, Sanjib K ; Anderson, Thomas ; Chang, Cheng-Wei T ; Takemoto, Jon Y ; Oblad, John ; Dhiman, Christine

Several azoles are widely used to treat human fungal infections. Increasing resistance to these azoles has prompted exploration of their synergistic antifungal activities when combined with other agents. The amphiphilic aminoglycoside, K20, was recently shown to inhibit filamentous fungi, yeasts and heterokonts, but not bacteria. In this study, in vitro synergistic growth inhibition by combinations of K20 and azoles (fluconazole, itraconazole, voriconazole, clotrimazole, or posaconazole) were examined against Candida species and Cryptococcus neoformans. Checkerboard microbroth dilution, time-kill curve, and disk diffusion assays revealed that K20 has synergistic inhibitory activities with all five azoles against C. albicans including azole-resistant C. albicans strains ATCC 64124 and ATCC 10231. Four (fluconazole, itraconazole, clotrimazole, posaconazole) and three (fluconazole, itraconazole, voriconazole) azoles were synergistically inhibitory with K20 against C. lusitaniae and C. tropicalis, respectively. Only posaconazole showed synergy with K20 against two Cryptococcus neoformans strains (90-26 and VR-54). Time-kill curves with azole-resistant C. albicans 64124 and azole-sensitive C. albicans MYA-2876 confirmed the K20-azole synergistic interactions with a ≥ 2 log10 decrease in colony-forming units (CFU)/ml compared with the corresponding azoles alone. These results suggest that combinations of K20 and azoles offer a possible strategy for developing therapies against candidiasis.

15 Jun 2015·Chemistry – A European JournalQ2 · CHEMISTRY

A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up‐regulating p27^KIP1

Q2 · CHEMISTRY

Article

Author: Turton, David ; Das, Amitava ; Thomas, Jim A ; Gill, Martin R ; Jarman, Paul J ; Smythe, Carl ; Ramu, Vadde

AbstractCytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear RuII–PtII complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]3+ (tpy=2,2′:6′,2′′‐terpyridine and tpypma=4‐([2,2′:6′,2′′‐terpyridine]‐4′‐yl)‐N‐(pyridin‐2‐ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell‐free conditions, VR54 binds DNA by non‐intercalative reversible mechanisms (Kb=1.3×105 M−1) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross‐resistance in the A2780CIS cisplatin‐resistant cell line. Through the preparation of mononuclear RuII and PtII structural derivatives it was determined that both metal centres are required for this anti‐proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA‐damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up‐regulating the cyclin‐dependent kinase inhibitor p27KIP1 and inhibiting retinoblastoma protein phosphorylation, which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal‐coordination compound to demonstrate such activity.

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Indication	Highest Phase	Country/Location	Organization	Date
Ovarian Cancer	Discovery	GB	The University of Sheffield	-
Ovarian Cancer	Discovery	GB	University of Oxford	-

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