Harnessing biocatalysis as a green tool in antibiotic synthesis and discovery.

Biocatalysis offers a sustainable approach to drug synthesis, leveraging the high selectivity and efficiency of enzymes. This review explores the application of biocatalysis in the early-stage synthesis of antimicrobial compounds, emphasizing its advantages over traditional chemical methods. We discuss various biocatalysts, including enzymes and whole-cell systems, and their role in the selective functionalization and preparation of antimicrobials and antibacterial building blocks.

Impact of molecular symmetry on crystallization pathways in highly supersaturated KHPO solutions.

Solute structure and its evolution in supersaturated aqueous solutions are key clues to understand Ostwald's step rule. Here, we measure the structural evolution of solute molecules in highly supersaturated solutions of KHPO (KDP) and NHHPO (ADP) using a combination of electrostatic levitation and synchrotron X-ray scattering. The measurement reveals the existence of a solution-solution transition in KDP solution, caused by changing molecular symmetries and structural evolution of the solution with supersaturation.

Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics.

A new class of amphiphilic molecules, the lipoguanidines, designed as hybrids of guanidine and fatty acid compounds, has been synthesized and developed. The new molecules present both a guanidine polar head and a lipophilic tail that allow them to disrupt bacterial membranes and to sensitize Gram-negative bacteria to the action of the narrow-spectrum antibiotics rifampicin and novobiocin. The lipoguanidine sensitizes , , , and to rifampicin, thereby reducing the antibiotic minimum inhibitory concentrations (MIC) up to 256-fold.

Simultaneous measurements of volume, pressure, optical images, and crystal structure with a dynamic diamond anvil cell: A real-time event monitoring system.

The dynamic diamond anvil cell (dDAC) technique has attracted great interest because it possibly provides a bridge between static and dynamic compression studies with fast, repeatable, and controllable compression rates. The dDAC can be a particularly useful tool to study the pathways and kinetics of phase transitions under dynamic pressurization if simultaneous measurements of physical quantities are possible as a function of time. We here report the development of a real-time event monitoring (RTEM) system with dDAC, which can simultaneously record the volume, pressure, optical image, and structure of materials during dynamic compression runs.

Oxazolidinones as versatile scaffolds in medicinal chemistry.

Oxazolidinone is a five-member heterocyclic ring with several biological applications in medicinal chemistry. Among the three possible isomers, 2-oxazolidinone is the most investigated in drug discovery. Linezolid was pioneered as the first approved drug containing an oxazolidinone ring as the pharmacophore group.

Hydration breaking and chemical ordering in a levitated NaCl solution droplet beyond the metastable zone width limit: evidence for the early stage of two-step nucleation.

For over two decades, NaCl nucleation from a supersaturated aqueous solution has been predicted to occur a two-step nucleation (TSN) mechanism, , two sequential events, the formation of locally dense liquid regions followed by structural ordering. However, the formation of dense liquid regions in the very early stage of TSN has never been experimentally observed. By using a state-of-the-art technique, a combination of electrostatic levitation (ESL) and synchrotron X-ray and Raman scatterings, we find experimental evidence that indicates the formation of dense liquid regions in NaCl bulk solution at an unprecedentedly high level of supersaturation ( = 2.

Antimicrobial drugs bearing guanidine moieties: A review.

Compounds incorporating guanidine moieties constitute a versatile class of biologically interesting molecules with a wide array of applications. As such, guanidines have been exploited as privileged structural motifs in designing novel drugs for the treatment of various infectious and non-infectious diseases. In designing anti-infective agents, this moiety carries great appeal by virtue of attributes such as hydrogen-bonding capability and protonatability at physiological pH in the context of interaction with biological targets.

Development of photoactivable phenanthroline-based manganese(I) CO-Releasing molecules (PhotoCORMs) active against ESKAPE bacteria and bacterial biofilms.

The synthesis and biological evaluation of a series of phenanthroline-based visible-light-activated manganese(I) carbon-monoxide-releasing molecules (PhotoCORMs) against ESKAPE bacteria and bacterial biofilms is reported. Four carbonyl compounds of general formula fac-[Mn(NN)(CO)(L)] have been synthesized and characterized. Despite being thermally stable in the absence of light, these PhotoCORMs readily release CO upon blue (435-450 nm) LED light irradiation as confirmed by spectrophotometric CO releasing experiments (Mb Assay).

A mild and chemoselective CALB biocatalysed synthesis of sulfoxides exploiting the dual role of AcOEt as solvent and reagent.

A mild, chemoselective and sustainable biocatalysed synthesis of sulfoxides has been developed exploiting CALB and using AcOEt with a dual role of more environmentally friendly reaction solvent and enzyme substrate. A series of sulfoxides, including the drug omeprazole, have been synthesised in high yields and with excellent E-factors.

Universal field-tunable terahertz emission by ultrafast photoinduced demagnetization in Fe, Ni, and Co ferromagnetic films.

We report a universal terahertz (THz) emission behavior from simple Ni, Fe, and Co metallic ferromagnetic films, triggered by the femtosecond laser pulse and subsequent photoinduced demagnetization on an ultrafast time scale. THz emission behavior in ferromagnetic films is found to be consistent with initial magnetization states controlled by external fields, where the hysteresis of the maximal THz emission signal is observed to be well-matched with the magnetic hysteresis curve. It is experimentally demonstrated that the ultrafast THz emission by the photoinduced demagnetization is controllable in a simple way by external fields as well as pump fluences.

Structure of Penta-Alanine Investigated by Two-Dimensional Infrared Spectroscopy and Molecular Dynamics Simulation.

We have studied the structure of (Ala)5, a model unfolded peptide, using a combination of 2D IR spectroscopy and molecular dynamics (MD) simulation. Two different isotopomers, each bis-labeled with (13)C═O and (13)C═(18)O, were strategically designed to shift individual site frequencies and uncouple neighboring amide-I' modes. 2D IR spectra taken under the double-crossed ⟨π/4, -π/4, Y, Z⟩ polarization show that the labeled four-oscillator systems can be approximated by three two-oscillator systems.

Ion aggregation in high salt solutions. III. Computational vibrational spectroscopy of HDO in aqueous salt solutions.

The vibrational frequency, frequency fluctuation dynamics, and transition dipole moment of the O-D stretch mode of HDO molecule in aqueous solutions are strongly dependent on its local electrostatic environment and hydrogen-bond network structure. Therefore, the time-resolved vibrational spectroscopy the O-D stretch mode has been particularly used to investigate specific ion effects on water structure. Despite prolonged efforts to understand the interplay of O-D vibrational dynamics with local water hydrogen-bond network and ion aggregate structures in high salt solutions, still there exists a gap between theory and experiment due to a lack of quantitative model for accurately describing O-D stretch frequency in high salt solutions.

Simultaneous spectral and temporal analyses of kinetic energies in nonequilibrium systems: theory and application to vibrational relaxation of O-D stretch mode of HOD in water.

A time series of kinetic energies (KE) from classical molecular dynamics (MD) simulation contains fundamental information on system dynamics. It can also be analyzed in the frequency domain through Fourier transformation (FT) of velocity correlation functions, providing energy content of different spectral regions. By limiting the FT time span, we have previously shown that spectral resolution of KE evolution is possible in the nonequilibrium situations [Jeon and Cho, J.

Ion aggregation in high salt solutions: ion network versus ion cluster.

The critical aggregation phenomena are ubiquitous in many self-assembling systems. Ions in high salt solutions could also spontaneously form larger ion aggregates, but their effects on hydrogen-bond structures in water have long been controversial. Here, carrying out molecular dynamics (MD) simulation studies of high salt solutions and comparing the MD simulation results with infrared absorption and pump-probe spectroscopy of O-D stretch mode of HDO in highly concentrated salt solutions and (13)C-NMR chemical shift of S(13)CN(-) in KSCN solutions, we find evidence on the onset of ion aggregate and large-scale ion-ion network formation that concomitantly breaks water hydrogen-bond structure in certain salt solutions.

Direct observation of ligand rebinding pathways in hemoglobin using femtosecond mid-IR spectroscopy.

The dynamics of NO rebinding in hemoglobin (Hb) was directly observed using femtosecond mid-IR spectroscopy after photodeligation of NO from HbNO in D(2)O at 283 K. Time-resolved spectra of bound NO appeared to have a single feature peaked at 1616 cm(-1) but were much better described by two Gaussians with equal intensities but different rebinding kinetics, where the feature at 1617 cm(-1) rebinds faster than the one at 1614 cm(-1). It is possible that the two bands each correspond to one of two subunit constituents of the tetrameric Hb.

Protein conformation-controlled rebinding barrier of NO and its binding trajectories in myoglobin and hemoglobin at room temperature.

The effect of the solvent viscosity on the dynamics of NO rebinding to myoglobin (Mb) and hemoglobin (Hb) was examined by femtosecond (fs) time-resolved vibrational spectroscopy after photodeligation of NO from MbNO and HbNO in various viscous solutions at 283 K using a 580 nm excitation pulse. The rebinding kinetics of NO to both Mb and Hb were nonexponential, but their dependence on the solvent viscosity was different. The rate of NO rebinding to Mb increased with increasing solution viscosity, which was achieved by increasing the glycerol content in glycerol/water mixture.

Native and unfolded cytochrome c--comparison of dynamics using 2D-IR vibrational echo spectroscopy.

Unfolded vs native CO-coordinated horse heart cytochrome c (h-cyt c) and a heme axial methionine mutant cyt c552 from Hydrogenobacter thermophilus ( Ht-M61A) are studied by IR absorption spectroscopy and ultrafast 2D-IR vibrational echo spectroscopy of the CO stretching mode. The unfolding is induced by guanidinium hydrochloride (GuHCl). The CO IR absorption spectra for both h-cyt c and Ht-M61A shift to the red as the GuHCl concentration is increased through the concentration region over which unfolding occurs.

Direct observation of fast protein conformational switching.

Folded proteins can exist in multiple conformational substates. Each substate reflects a local minimum on the free-energy landscape with a distinct structure. By using ultrafast 2D-IR vibrational echo chemical-exchange spectroscopy, conformational switching between two well defined substates of a myoglobin mutant is observed on the approximately 50-ps time scale.

Disulfide bond influence on protein structural dynamics probed with 2D-IR vibrational echo spectroscopy.

Intramolecular disulfide bonds are understood to play a role in regulating protein stability and activity. Because disulfide bonds covalently link different components of a protein, they influence protein structure. However, the effects of disulfide bonds on fast (subpicosecond to approximately 100 ps) protein equilibrium structural fluctuations have not been characterized experimentally.

Neuroglobin dynamics observed with ultrafast 2D-IR vibrational echo spectroscopy.

Neuroglobin (Ngb), a protein in the globin family, is found in vertebrate brains. It binds oxygen reversibly. Compared with myoglobin (Mb), the amino acid sequence has limited similarity, but key residues around the heme and the classical globin fold are conserved in Ngb.

Probing dynamics of complex molecular systems with ultrafast 2D IR vibrational echo spectroscopy.

Ultrafast 2D IR vibrational echo spectroscopy is described and a number of experimental examples are given. Details of the experimental method including the pulse sequence, heterodyne detection, and determination of the absorptive component of the 2D spectrum are outlined. As an initial example, the 2D spectrum of the stretching mode of CO bound to the protein myoglobin (MbCO) is presented.

Substrate binding and protein conformational dynamics measured by 2D-IR vibrational echo spectroscopy.

Enzyme structural dynamics play a pivotal role in substrate binding and biological function, but the influence of substrate binding on enzyme dynamics has not been examined on fast time scales. In this work, picosecond dynamics of horseradish peroxidase (HRP) isoenzyme C in the free form and when ligated to a variety of small organic molecule substrates is studied by using 2D-IR vibrational echo spectroscopy. Carbon monoxide bound at the heme active site of HRP serves as a spectroscopic marker that is sensitive to the structural dynamics of the protein.

Effects of solvent viscosity on ligand interconversion dynamics in the primary docking site of heme proteins.

Interconversion dynamics of the ligand in the primary docking site of myoglobin (Mb) and hemoglobin (Hb) in trehalose and glycerol/D2O mixtures at 283 K was investigated by probing time-resolved vibrational spectra of CO photolyzed from these proteins. The interconversion dynamics in viscous media are similar to those in aqueous solution, indicating that it is minimally coupled to the solvent-coupled large-scale protein motion. Interconversion rates in the heme pocket of Hb in water solution are slower than those of Mb in trehalose glass, suggesting that the interconversion barrier in Hb is intrinsically higher than that in Mb and is not modified by the solvent viscosity.

Protein conformation-induced modulation of ligand binding kinetics: a femtosecond mid-IR study of nitric oxide binding trajectories in myoglobin.

By directly probing the photolyzed NO from MbNO at physiological conditions, the rebinding trajectories of the photoproduct were obtained, from which we found that a time-dependent barrier arising from protein relaxation on the same time scale as that of the rebinding process is responsible for the NO nonexponential rebinding.

Picosecond dynamics of ligand interconversion in the primary docking site of heme proteins.

We have used femtosecond IR spectroscopy to probe interconversion dynamics of ligand in the primary docking site of heme proteins under physiological conditions. The docking site, fashioned with highly conserved amino acid residues, modulates ligand-binding activity by mediating the passage of ligand to and from the active binding site. Ligands in two states of the docking site interconvert on the picosecond time scale, and the rates are about 4 times slower in hemoglobin than that in myoglobin.