Bactericidal disruption of magnesium metallostasis in Mycobacterium tuberculosis is counteracted by mutations in the metal ion transporter CorA

A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis. A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis. Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds’ cidality against replicating M. tuberculosis. These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds

In Vitro and in Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide)

Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium tuberculosis

The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 β-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3′ that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a β-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A β-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent β-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states

Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition

Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology

Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents

Durability of a lightweight construction material made with dune sand and expanded polystyrene

International audienceThe partial/total substitution of ordinary aggregates by other unused local materials in order to produce new lightweight concretes/mortars is an interesting alternative that can solve technical, economical and environmental problems. On the other hand, the replacement of cement by other binders in the elaboration of concretes and mortars can also provide other properties and benefits more important and more interesting. In this context, previous works have been undertaken and have shown the possibility and the effectiveness of the use of expanded polystyrene aggregates and dune sands on the physicomechanical properties of plaster mortars, especially in term of lightness and thermal insulation. Our current concern is to know: how this composite will behave in certain aggressive environments. Therefore, the main objective of the present work is to study the effect of some chemical environments on the behaviour of a plaster mortar based on dune sands and expanded polystyrene beads. For this study, three different environments have been envisaged: demineralised water (as reference), sulphuric acid solution and magnesium sulphate solution. The obtained results showed that although the surface of the studied samples seems to be degraded, in their interior, the material appears more homogeneous and compact with relatively a good adhesion sand/plaster and EPS/plaster. The presence of the acid or the sulphate in water does not increase the water effect; besides, the acid considerably improves its effect in compression

SwissParam 2023: A Modern Web-Based Tool for Efficient Small Molecule Parametrization.

Most steps of drug discovery are now routinely supported and accelerated by computer-aided drug design tools. Among them, structure-based approaches use the three-dimensional structure of the targeted biomacromolecule as a major source of information. When it comes to calculating the interactions of small molecules with proteins using the equations of molecular mechanics, topologies, atom typing, and force field parameters are required. However, generating parameters for small molecules remains challenging due to the large number of existing chemical groups. The SwissParam web tool was first released in 2011 with the aim of generating parameters and topologies for small molecules based on the Merck molecular force field (MMFF) while being compatible with the CHARMM22/27 force field. Here, we present an updated version of SwissParam, providing various new features, including the possibility to setup covalent ligands. Molecules can now be imported from different file formats or via a molecular sketcher. The MMFF-based approach has been updated to provide parameters and topologies compatible with the CHARMM36 force field. An option was added to generate small molecule parametrizations following the CHARMM General Force Field via the multipurpose atom-typer for CHARMM (MATCH) approach. Additionally, SwissParam now generates information on probable alternative tautomers and protonation states of the query molecule so that the user can consider all microspecies relevant to its compound. The new version of SwissParam is freely available at www.swissparam.ch and can also be accessed through a newly implemented command-line interface

SwissDock 2024: major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina.

Drug discovery aims to identify potential therapeutic compounds capable of modulating the activity of specific biological targets. Molecular docking can efficiently support this process by predicting binding interactions between small molecules and macromolecular targets and potentially accelerating screening campaigns. SwissDock is a computational tool released in 2011 as part of the SwissDrugDesign project, providing a free web-based service for small-molecule docking after automatized preparation of ligands and targets. Here, we present the latest version of SwissDock, in which EADock DSS has been replaced by two state-of-the-art docking programs, i.e. Attracting Cavities and AutoDock Vina. AutoDock Vina provides faster docking predictions, while Attracting Cavities offers more accurate results. Ligands can be imported in various ways, including as files, SMILES notation or molecular sketches. Targets can be imported as PDB files or identified by their PDB ID. In addition, advanced search options are available both for ligands and targets, giving users automatized access to widely-used databases. The web interface has been completely redesigned for interactive submission and analysis of docking results. Moreover, we developed a user-friendly command-line access which, in addition to all options of the web site, also enables covalent ligand docking with Attracting Cavities. The new version of SwissDock is freely available at https://www.swissdock.ch/

Suivi de l’endommagement en fatigue d’un composite à renfort interlock carbone/époxy par émission acoustique

International audienc

A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis.

Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73 ± 0.24 Log10 CFU and 2.68 ± Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy