Machine Learning Prediction of Small Molecule Accumulation in Enhanced with Descriptor Statistics.

Antibiotic resistance, particularly among Gram-negative bacteria, poses a significant healthcare challenge due to their ability to evade antibiotic action through various mechanisms. In this study, we explore the prediction of small molecule accumulation in Gram-negative bacteria by using machine learning techniques enhanced with statistical descriptors derived from molecular dynamics simulations. We begin by identifying a minimal set of molecular descriptors that maximize the model's predictive power while preserving human interpretability.

Physico-Chemical Investigation and Antimicrobial Efficacy of Ozonated Oils: The Case Study of Commercial Ozonated Olive and Sunflower Seed Refined Oils.

Drug resistance represents one of the great plagues of our time worldwide. This largely limits the treatment of common infections and requires the development of new antibiotics or other alternative approaches. Noteworthy, the indiscriminate use of antibiotics is mostly responsible for the selection of mutations that confer drug resistance to microbes.

The combination of inorganic phosphate and pyrophosphate P-NMR for the electrodeless pH determination in the 5-12 range.

Potentiometry is the primary pH measurement method, but alternatives are sought beyond glass electrodes operative limitations. In nuclear magnetic resonance (NMR) experiments, electrodeless pH sensing is important to track changes along titrations, during chemical reactions or inside compartmentalized environments inaccessible to electrodes, for instance. Although several interesting NMR pH indicators have been already presented, the potential of inorganic phosphate is overlooked, despite its common presence in NMR samples as the buffer main component.

Benzothiazole DNA gyrase inhibitors and their conjugates with siderophore mimics: design, synthesis and evaluation.

Benzothiazole-based bacterial DNA gyrase and topoisomerase IV inhibitors are promising new antibacterial agents with potent activity against Gram-positive and Gram-negative bacterial strains. The aim of this study was to improve the uptake of these inhibitors into the cytoplasm of Gram-negative bacteria by conjugating them to the small siderophore mimics. The best conjugate 18b displayed potent DNA gyrase and topoisomerase IV inhibition.

Glyphosate sensing in aqueous solutions by fluorescent zinc(II) complexes of [9]aneN-based receptors.

Herein we describe the binding abilities of Zn(II) complexes of [12]aneN- (L1) and [9]aneN-based receptors (L2, L3) towards the herbicides -(phosphonomethyl)glycine (glyphosate, HPMG) and 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid (glufosinate, HGLU), and also aminomethylphosphonic acid (HAMPA), the main metabolite of HPMG, and phosphate. All ligands form stable Zn(II) complexes, whose coordination geometries allow a possible interaction of the metal center with exogenous anionic substrates. Potentiometric studies evidenced the marked coordination ability of the L2/Zn(II) system for the analytes considered, with a preferential binding affinity for HPMG over the other substrates, in a wide range of pH values.

A Simulation Model for the Non-Electrogenic Uniport Carrier-Assisted Transport of Ions across Lipid Membranes.

Impressive work has been completed in recent decades on the transmembrane anion transport capability of small synthetic transporters from many different structural classes. However, very few predicting models have been proposed for the fast screening of compound libraries before spending time and resources on the laboratory bench for their synthesis. In this work, a new approach is presented which aims at describing the transport process by taking all the steps into explicit consideration, and includes all possible experiment-derived parameters.

A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs).

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs).

Can Serendipity Still Hold Any Surprises in the Coordination Chemistry of Mixed-Donor Macrocyclic Ligands? The Case Study of Pyridine-Containing 12-Membered Macrocycles and Platinum Group Metal Ions Pd, Pt, and Rh.

This study investigates the coordination chemistry of the tetradentate pyridine-containing 12-membered macrocycles - towards Platinum Group metal ions Pd, Pt, and Rh. The reactions between the chloride salts of these metal ions and the three ligands in MeCN/HO or MeOH/HO (1:1 /) are shown, and the isolated solid compounds are characterized, where possible, by mass spectroscopy and H- and C-NMR spectroscopic measurements. Structural characterization of the 1:1 metal-to-ligand complexes [Pd()Cl][PdCl], [Pt()Cl](BF), [Rh()Cl](PF), and [Rh()Cl](BF)·MeCN shows the coordinated macrocyclic ligands adopting a folded conformation, and occupying four coordination sites of a distorted square-based pyramidal and octahedral coordination environment for the Pd/Pt, and Rh complexes, respectively.

Conformational change following conversion of inactive rhinophrynin-33 to bioactive rhinophrynin-27 in the skin of the frog Rhinophrynus dorsalis.

Skin secretions of the Mexican burrowing toad Rhinophrynus dorsalis (Rhinophrynidae) contain the proline-arginine-rich peptide, rhinophrynin-27 (RP-27; ELRLPEIARPVPEVLPARLPLPALPRN) with insulinotropic and immunomodulatory properties, together with a higher concentration of the biologically inactive form, rhinophrynin-33 (RP-33) that constitutes RP-27 extended from its C-terminus by the hexapeptide KMAKNQ. Determination of the conformation of RP-33 by NMR demonstrates that in both water and in a solvent that promotes protein folding (50% trifluoroethanol-water), the majority of the proline residues are found in a polyproline type II helical region. The peptide adopts a horseshoe (U-shaped) conformation with pronounced bends in the molecule of around 100°-120° at Glu and Arg.

Permeation of β-Lactamase Inhibitors through the General Porins of Gram-Negative Bacteria.

Modern medicine relies upon antibiotics, but we have arrived to the point where our inability to come up with new effective molecules against resistant pathogens, together with the declining private investment, is resulting in the number of untreatable infections increasing worldwide at worrying pace. Among other pathogens, widely recognized institutions have indicated Gram-negative bacteria as particularly challenging, due to the presence of the outer membrane. The very first step in the action of every antibiotic or adjuvant is the permeation through this membrane, with small hydrophilic drugs usually crossing through protein channels.

Simple squaramide receptors for highly efficient anion binding in aqueous media and transmembrane transport.

A family of acyclic squaramide receptors (L1-L5) have been synthesised with the aim to bind anions in a competitive solvent mixture and to evaluate how the presence of additional H-bond donor groups on the squaramide scaffold could affect the affinity towards anions and the transmembrane transport ability.

Aza- and Mixed Thia/Aza-Macrocyclic Receptors with Quinoline-Bearing Pendant Arms for Optical Discrimination of Zinc(II) or Cadmium(II) Ions.

The synthesis and coordination properties of two fluorescent chemosensors, featuring [9]aneN (1,4,7-triazacyclononane; L1) and [12]aneNS (1-aza-4,7,10-trithiacyclododecane; L2) as receptor units, and a quinoline pendant arm with an amide group as a functional group spacer are described. The optical responses of L1 and L2 in the presence of several metal ions were analysed in MeCN/H O (1 : 4 v/v) solutions. A selective chelation enhancement of fluorescence (CHEF) effect was observed in the presence of Zn in the case of L1, and in the presence of Cd in the case of L2, following the formation of a 1 : 1 and a 1 : 2 metal/ligand complex, respectively, which was also confirmed by potentiometric measurements.

Conformational analysis and in vitro immunomodulatory and insulinotropic properties of the frog skin host-defense peptide rhinophrynin-27 and selected analogs.

The study investigates conformational analysis and the in vitro cytokine-mediated immunomodulatory and insulin-releasing activities of rhinophrynin-27 (ELRLPEIARPVPEVLPARLPLPALPRN; RP-27), a proline-arginine-rich peptide first isolated from skin secretions of the Mexican burrowing toad Rhinophrynus dorsalis (Rhinophrynidae). In both water and 50% trifluoroethanol-water, the peptide adopts a polyproline type II helical conformation with a high degree of deviation from the canonical collagen-like folding and a pronounced bend in the molecule at the Glu residue. Incubation of mouse peritoneal cells with RP-27 significantly (P < 0.

[9]aneN-based fluorescent receptors for metal ion sensing, featuring urea and amide functional groups.

We describe here the synthesis and coordination properties of three new derivatives of [9]aneN3 containing phenyl/quinoline pendant arm derivatives (L1, L2 and L3, respectively) also featuring urea (L1-L2) or amide (L3) functions as "non-innocent" spacers. At first, L1, L2 and L3 were studied considering the interaction with a series of anions (AcO-, BzO-, H2PO4-, F-, and Cl-) by means of 1H NMR measurements. Subsequently, the optical responses of L2 and L3 in the presence of several metal ions Cd2+, Co2+, Cu2+, Fe3+, Hg2+, K+, Mg2+, Mn2+, Ni2+, Zn2+ and Pb2 were analysed in MeCN/H2O (4 : 1 v/v).

Complexes formed by the siderophore-based monosulfactam antibiotic BAL30072 and their interaction with the outer membrane receptor PiuA of P. aeruginosa.

Nuclear magnetic resonance and infrared spectroscopy have been used to investigate the formation of complexes of BAL30072 with Fe and Ga in solution and to collect geometrical parameters supporting reliable 3D structure models. Structural models for the ligand-metal complexes with different stoichiometries have been characterized using density functional theory calculations. Blind ensemble docking to the PiuA receptor from P.

Preacinetobactin not acinetobactin is essential for iron uptake by the BauA transporter of the pathogen .

New strategies are urgently required to develop antibiotics. The siderophore uptake system has attracted considerable attention, but rational design of siderophore antibiotic conjugates requires knowledge of recognition by the cognate outer-membrane transporter. is a serious pathogen, which utilizes (pre)acinetobactin to scavenge iron from the host.

Folded Structure and Membrane Affinity of the N-Terminal Domain of the Three Human Isoforms of the Mitochondrial Voltage-Dependent Anion-Selective Channel.

Voltage-dependent anion-selective channels (VDACs) are primarily located in the mitochondrial outer membrane (MOM). They are essential for the regulation of ion and metabolite exchanges. In particular, their role in energy-related nucleotide exchange has many implications in apoptosis, cancer, and neurodegenerative diseases.

Effects of amphipathic profile regularization on structural order and interaction with membrane models of two highly cationic branched peptides with β-sheet propensity.

Antimicrobial peptides attracted increasing interest in last decades due to the rising concern of multi-drug resistant pathogens. Dendrimeric peptides are branched molecules with multiple copies of one peptide functional unit bound to the central core. Compared to linear analogues, they usually show improved activity and lower susceptibility to proteases.

Nanostructure of Surface Films on Ni18P Alloy in Sulfate Solutions by the Maximum Entropy Method.

NiP alloys are very often used in industry, due to their outstanding performance in corrosion and wear. Alloys with high phosphorus content (≥16 atom % P) are amorphous and show high corrosion resistance in both neutral and acidic solutions irrespective of the presence of chloride ions. The reason for this behavior is attributed to the formation of a "P-enriched surface layer" whose exact nature is still under debate.

The Semi-Synthetic Peptide Lin-SB056-1 in Combination with EDTA Exerts Strong Antimicrobial and Antibiofilm Activity against Pseudomonas aeruginosa in Conditions Mimicking Cystic Fibrosis Sputum.

is a major cause of chronic lung infections in cystic fibrosis (CF) patients. The ability of the bacterium to form biofilms and the presence of a thick and stagnant mucus in the airways of CF patients largely contribute to antibiotic therapy failure and demand for new antimicrobial agents able to act in the CF environment. The present study investigated the anti- activity of lin-SB056-1, a recently described semi-synthetic antimicrobial peptide, used alone and in combination with the cation chelator ethylenediaminetetraacetic acid (EDTA).

Bacterial Outer Membrane Porins as Electrostatic Nanosieves: Exploring Transport Rules of Small Polar Molecules.

Transport of molecules through biological membranes is a fundamental process in biology, facilitated by selective channels and general pores. The architecture of some outer membrane pores in Gram-negative bacteria, common to other eukaryotic pores, suggests them as prototypes of electrostatically regulated nanosieve devices. In this study, we sensed the internal electrostatics of the two most abundant outer membrane channels of Escherichia coli, using norfloxacin as a dipolar probe in single molecule electrophysiology.

Antimicrobial Dendrimeric Peptides: Structure, Activity and New Therapeutic Applications.

Microbial resistance to conventional antibiotics is one of the most outstanding medical and scientific challenges of our times. Despite the recognised need for new anti-infective agents, however, very few new drugs have been brought to the market and to the clinic in the last three decades. This review highlights the properties of a new class of antibiotics, namely dendrimeric peptides.

General Method to Determine the Flux of Charged Molecules through Nanopores Applied to β-Lactamase Inhibitors and OmpF.

A major challenge in the discovery of the new antibiotics against Gram-negative bacteria is to achieve sufficiently fast permeation in order to avoid high doses causing toxic side effects. So far, suitable assays for quantifying the uptake of charged antibiotics into bacteria are lacking. We apply an electrophysiological zero-current assay using concentration gradients of β-lactamase inhibitors combined with single-channel conductance to quantify their flux rates through OmpF.

Rationalizing the permeation of polar antibiotics into Gram-negative bacteria.

The increasing level of antibiotic resistance in Gram-negative bacteria, together with the lack of new potential drug scaffolds in the pipeline, make the problem of infectious diseases a global challenge for modern medicine. The main reason that Gram-negative bacteria are particularly challenging is the presence of an outer cell-protecting membrane, which is not present in Gram-positive species. Such an asymmetric bilayer is a highly effective barrier for polar molecules.

The singular behavior of a β-type semi-synthetic two branched polypeptide: three-dimensional structure and mode of action.

Dendrimeric peptides make a versatile group of bioactive peptidomimetics and a potential new class of antimicrobial agents to tackle the pressing threat of multi-drug resistant pathogens. These are branched supramolecular assemblies where multiple copies of the bioactive unit are linked to a central core. Beyond their antimicrobial activity, dendrimeric peptides could also be designed to functionalize the surface of nanoparticles or materials for other medical uses.