Evaluating the druggability of TrmD, a potential antibacterial target, through design and microbiological profiling of a series of potent TrmD inhibitors.

The post-transcriptional modifier tRNA-(N1G37) methyltransferase (TrmD) has been proposed to be essential for growth in many Gram-negative and Gram-positive pathogens, however previously reported inhibitors show only weak antibacterial activity. In this work, optimisation of fragment hits resulted in compounds with low nanomolar TrmD inhibition incorporating features designed to enhance bacterial permeability and covering a range of physicochemical space. The resulting lack of significant antibacterial activity suggests that whilst TrmD is highly ligandable, its essentiality and druggability are called into question.

Restoring carbapenem efficacy: a novel carbapenem companion targeting metallo-ß-lactamases in carbapenem-resistant Enterobacterales.

BACKGROUND: The dissemination of MBLs compromises effective use of many ß-lactams in the treatment of patients with life-threatening bacterial infections. Predicted global increases in the prevalence of MBL-producing carbapenem-resistant Enterobacterales (CRE) are being realized, yielding infections that are untreatable with existing therapies including newly approved ß-lactam/ß-lactamase inhibitor combinations. Developing MBL inhibitors (MBLIs) now is essential to address the growing threat that MBL-producing CRE pose to patients. METHODS: A novel MBLI series was assessed by susceptibility testing and time-kill assays. Target activity and selectivity was evaluated using bacterial NDM, VIM and IMP enzyme assays and human matrix metallopeptidase enzyme assays, respectively, and cytotoxicity was assessed in HepG2 cells. In vivo efficacy of meropenem/MBLI combinations was evaluated in a mouse thigh infection model using an NDM-1-producing Escherichia coli strain. RESULTS: Combination of MBLIs with carbapenems reduced MICs for NDM/IMP/VIM-producing Enterobacterales by up to 128-fold compared with the carbapenems alone. Supplementation of meropenem with the promising compound 272 reduced the MIC90 from 128 to 0.25 mg/L in a panel of MBL-producing CRE clinical isolates (n = 115). Compound 272 restored the bactericidal activity of meropenem and was non-cytotoxic, potentiating the antimicrobial action of meropenem through specific inhibition of NDM, IMP and VIM. In vivo efficacy was achieved in a mouse thigh infection model with meropenem/272 dosed subcutaneously. CONCLUSIONS: We have developed a series of rationally designed MBLIs that restore activity of carbapenems against NDM/IMP/VIM-producing Enterobacterales. This series warrants further development towards a novel combination therapy that combats antibiotic-resistant organisms, which pose a critical threat to human health.

Metal ion levels and revision rates in metal-on-metal hip resurfacing arthroplasty: a comparative study.

Metal-on-metal (MoM) bearings in hip surgery are related to increased blood levels of metal ions. The nature of the relationship between ion levels and failure is still not fully understood. This study compares three cohorts of patients, 120 patients in each cohort, treated with a hip resurfacing arthroplasty, grouped by brand and diameter of femoral component on average four years postoperatively: Birmingham Hip Resurfacing ≥50 mm, Durom resurfacing ≥50 mm and Durom resurfacing <50 mm. The median blood ion levels of cobalt and chromium were significantly lower in the cohort with the large Durom resurfacing than the other two cohorts (P<0.05). The large BHR and large Durom HRA had revision rates of 3.3%. The small Durom HRA had a revision rate of 8.3%. Elevated blood ion levels can indicate a failing MoM bearing. The large BHR and large Durom HRA have similar revision rates yet the large Durom HRA had significantly lower metal ion levels. When similar ion levels were reported for BHR and small Durom the latter had significantly higher revision rates. This suggests ion levels do not absolutely predict the rate of HRA failure. Since MoM generation of metal ions is not the sole reason of failure, regular clinical and radiographic follow-up should also be in place for patients with these joints.

Light-emitting iridium complexes with tridentate ligands.

Once the Cinderella amongst the Platinum Group Metals at the Photochemistry Ball, iridium has become of intense interest since the beginning of the decade. Complexes of iridium(III) can be prepared that are highly luminescent, with emission wavelengths tuneable over the whole of the visible region. Whilst most studies have focused on tris-bidentate complexes, a rich and varied chemistry is also possible using tridentate ligands. In this review, we discuss the synthesis and excited-state properties of such complexes, exploring in particular how the number of cyclometallating carbon atoms in the coordination sphere of the metal ion influences the luminescence. Moving from [IrN6]3+ to [IrN3X3] coordination via [IrN5X]2+ and cis/trans-[IrN4X2]+ complexes, where N is a heterocyclic nitrogen and X is an anionic ligand or cyclometallated carbon, a whole range of luminescence efficiencies are encountered, ranging from the barely detectable to room temperature quantum yields approaching unity. We consider the extent to which these profound differences, arising as a result of subtle changes in molecular structure, can be rationalised in terms of the nature of the frontier orbitals.

Sensitization of europium(III) luminescence by benzophenone-containing ligands: regioisomers, rearrangements and chelate ring size, and their influence on quantum yields.

A series of europium(III) complexes based on the macrocyclic azacarboxylate structure, DO3A, have been investigated, incorporating benzophenone appended at N10 of the macrocycle via linkers containing amide bonds (H3DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid). Complexes [EuL(1-3)] incorporate N10-CH2CONH-BP linkers (BP = benzophenone), which allow formation of a five-membered chelate ring containing the metal ion upon chelation of the amide oxygen; these three isomeric complexes differ from one another in the substitution position of the BP unit, namely para, meta, and ortho for L1, L2, and L3 respectively. The quantum yields of europium luminescence sensitized via the chromophore are found to be highly dependent upon the position of substitution, being 20 times smaller for the ortho compared to the para-substituted complex. A related para-substituted BP complex [EuL(4)], prepared by an unusual Michael reaction of the azamacrocycle with a BP-containing acrylamide, incorporates an additional methylene unit in the linker, namely N10-CH2CH2CONH-BP. Despite the longer linker, this complex equals the luminescence quantum yield achieved with [EuL(1)] (Phi(lum) = 0.097 and 0.095, respectively, in H2O at 298 K). Analysis of the pertinent kinetics reveals that the decreased energy transfer efficiency in this complex, arising from the longer donor-acceptor distance, is compensated by an increased radiative rate constant. Under basic conditions, the ortho-substituted complex [EuL(3)] undergoes an intramolecular rearrangement to generate an unprecedented complex [EuL(5)] incorporating a 4-phenyl-2-hydroxyquinoline unit directly bound to the ring nitrogen. Although this complex is a poor emitter, an analogous complex obtained from 2-amino-acetophenone, which generates 4-methyl-2-hydroxyquinoline during the corresponding rearrangement, is an order of magnitude more emissive while still benefiting from relatively long-wavelength absorption. The emission from this complex is pH sensitive, being dramatically quenched under mildly basic conditions.

Luminescent complexes of iridium(III) containing N/\C/\N-coordinating terdentate ligands.

A family of bis-terdentate iridium(III) complexes is reported which contain a cyclometalated, N/\C[wedge]N-coordinating 1,3-di(2-pyridyl)benzene derivative. This coordination mode is favored by blocking competitive cyclometalation at the C4 and C6 positions of the ligand. Thus, 1,3-di(2-pyridyl)-4,6-dimethylbenzene (dpyxH) reacts with IrCl3 x 3H2O to generate a dichlorobridged dimer [Ir(dpyx-N,C,N)Cl(mu-Cl)]2, 1. This dimer is cleaved by DMSO to give [Ir(dpyx)(DMSO)Cl2], the X-ray crystal structure of which is reported here, confirming the N/\C/\N coordination mode of dpyx. The dimer 1 can also be cleaved by a variety of other ligands to generate novel classes of mononuclear complexes. These include charge-neutral bis-terdentate complexes of the form [Ir(N/\C/\N)(C/\N/\C)] and [Ir(N/\C/\N)(C/\N/\O)], by reaction of 1 with C/\N/\C-coordinating ligands (e.g., 2,6-diphenylpyridine and derivatives) and C/\N/\O-coordinating ligands (based on 6-phenylpicolinate), respectively. Treatment of 1 with terpyridines leads to dicationic complexes of the type [Ir(N/\C/\N)(N/\N/\N)]2+, while 2-phenylpyridine gives [Ir(dpyx-N/\C/\N)(ppy-C,N)Cl]. All of the charge-neutral complexes are luminescent in fluid solution at room temperature. Assignment of the emission to charge-transfer excited states with significant MLCT character is supported by DFT calculations. In the [Ir(N/\C/\N)(C/\N/\C)] class, fluorination of the C/\N/\C ligand at the phenyl 2' and 4' positions leads to a blue-shift in the emission and to an increase in the quantum yield (lambda(max) = 547 nm, phi = 0.41 in degassed CH(3)CN at 295 K) compared to the nonfluorinated parent complex (lambda(max) = 585 nm, phi = 0.21), as well as to a stabilization of the compound with respect to photodissociation through cleavage of mutually trans Ir-C bonds. [Ir(dpyx-N/\C/\N)(ppy-C,N)Cl] is an exceptionally bright emitter: phi = 0.76, lambda(max) = 508 nm, in CH(3)CN at 295 K. In contrast, the [Ir(N/\C/\N)(C/\N/\O)] complexes are much less emissive, shown to be due to fast nonradiative decay of the excited state, probably involving reversible Ir-O bond cleavage. The [Ir(N/\C/\N)(N/\N/\N)]2+ complexes are very feeble emitters even at 77 K, probably due to the almost exclusively interligand charge-transfer nature of the lowest-energy excited state in these complexes.

Synthesis and luminescence of a charge-neutral, cyclometalated iridium(III) complex containing N--C--N- and C--N--C-coordinating terdentate ligands.

The first examples of iridium(III) complexes containing a terdentate, N--C--N-coordinated 1,3-di(2-pyridyl)benzene derivative, cyclometalated at C2 of the benzene ring, are reported. This mode of binding becomes significant only if competitive cyclometalation at C4/C6 is blocked, and the ligand 1,3-di(2-pyridyl)-4,6-dimethylbenzene (dpyxH) has been prepared to achieve this condition. The charge-neutral complex [Ir(dpyx)(dppy)], 2, (dppyH(2) = 2,6-diphenylpyridine) has been isolated, containing dpyx and dppy bound to the metal through one and two carbon atoms, respectively. A terpyridyl analogue, [Ir(dpyx)(ttpy)](PF(6))(2), 3, (ttpy = 4'-tolylterpyridine) has also been prepared and its X-ray crystal structure determined, confirming the N--C--N binding mode of dpyx. Complex 2 emits strongly in degassed solution at 295 K (lambda(max) = 585 nm, phi = 0.21, tau = 3900 ns, in CH(3)CN). In solution, the excited state can also undergo photodissociation, through cleavage of one of the Ir-C(dppy) bonds.