Sustainable Joullié-Ugi and Continuous Flow Implementation Led to Novel Captopril-Inspired Broad-Spectrum Metallo-β-Lactamase Inhibitors.

Metallo-β-lactamases (MBL) production is one of the most alarming bacterial resistance mechanisms, conferring broad-spectrum resistance to most β-lactam antibiotics and combinations with β-lactamase inhibitors. Since no MBL inhibitors have been approved yet, the quest for novel, safe, and effective compounds, possibly endowed with broad-spectrum activity against clinically relevant MBLs, represents an urgent clinical need. Inspired by captopril, which behaves as a weak MBL inhibitor, we herein report a continuous flow protocol for the generation of new MBL inhibitors.

SAND: a comprehensive annotation of class D β-lactamases using structural alignment-based numbering.

Class D β-lactamases are a diverse group of enzymes that contribute to antibiotic resistance by inactivating β-lactam antibiotics. Examination of class D β-lactamases has evolved significantly over the years, with advancements in molecular biology and structural analysis providing deeper insights into their mechanisms of action and variation in specificity. However, one of the challenges in the field is the inconsistent residue numbering and secondary structure annotation across different studies, which complicates the comparison and interpretation of data.

Extract as a Source of Antimicrobial Compounds: A Circular Bioeconomy Approach.

The circular bioeconomy is currently a promising model for repurposing natural sources; these sources include plants due to their abundance of bioactive compounds. This study evaluated the antimicrobial properties of a extract. is an invasive macroalga from the Orbetello Lagoon (Tuscany, Italy), which grows in nutrient-rich environments and has been forming extended mats since 2005.

Synthesis of β-lactam-zidovudine pronucleosides as potential selective narrow-spectrum antibacterial agents.

Since the discovery of penicillin, the forerunner of the most widely used class of antibiotics ( β-lactams), natural compounds and their derivatives represented a major source of antibacterial therapeutic products whose availability enabled modern medical practices (invasive surgery, organ transplant, .). However, the relentless emergence of resistant bacteria is challenging the long-term efficacy of antibiotics, also decreasing their economic attractiveness for big pharma, leading to a significant decay in antibacterial development in the 21 century and an increased use of last-resort drugs such as carbapenems or colistin.

An update on antibacterial AlkylGuanidino Ureas: Design of new derivatives, synergism with colistin and data analysis of the whole library.

Antimicrobial resistance (AMR) represents one of the most challenging global Public Health issues, with an alarmingly increasing rate of attributable mortality. This scenario highlights the urgent need for innovative medicinal strategies showing activity on resistant isolates (especially, carbapenem-resistant Gram-negative bacteria, methicillin-resistant S. aureus, and vancomycin-resistant enterococci) yielding new approaches for the treatment of bacterial infections.

Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases.

Background: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools.

Aurones and derivatives as promising New Delhi metallo-β-lactamase (NDM-1) inhibitors.

Bacterial resistance is undoubtedly one of the main public health concerns especially with the emergence of metallo-β-lactamases (MBLs) able to hydrolytically inactivate β-lactam antibiotics. Currently, there are no inhibitors of MBLs in clinical use to rescue antibiotic action and the New Delhi metallo-β-lactamase-1 (NDM-1) is still considered as one of the most relevant targets for inhibitor development. Following a fragment-based strategy to find new NDM-1 inhibitors, we identified aurone as a promising scaffold.

Discovering NDM-1 inhibitors using molecular substructure embeddings representations.

NDM-1 (New-Delhi-Metallo-β-lactamase-1) is an enzyme developed by bacteria that is implicated in bacteria resistance to almost all known antibiotics. In this study, we deliver a new, curated NDM-1 bioactivities database, along with a set of unifying rules for managing different activity properties and inconsistencies. We define the activity classification problem in terms of Multiple Instance Learning, employing embeddings corresponding to molecular substructures and present an ensemble ranking and classification framework, relaying on a k-fold Cross Validation method employing a per fold hyper-parameter optimization procedure, showing promising generalization ability.

Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases.

Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this article, we investigate a new approach to negate bacterial resistance: exploit the β-lactam bond cleavage by β-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm.

Nucleoside Derivatives of 2,6-Diaminopurine Antivirals: Base-Modified Nucleosides with Broad-Spectrum Antimicrobial Properties.

The plethora of viral outbreaks experienced in the last decade, together with the widespread distribution of many re-emerging and newly emerging viruses, emphasize the urgent need for novel broad-spectrum antivirals as tools for early intervention in case of future epidemics. Non-natural nucleosides have been at the forefront for the treatment of infectious diseases for many years and still represent one of the most successful classes of antiviral molecules on the market. In the attempt to explore the biologically relevant chemical space of this class of antimicrobials, we describe herein the development of novel base-modified nucleosides by converting previously identified 2,6-diaminopurine antivirals into the corresponding D/L ribonucleosides, acyclic nucleosides and prodrug derivatives.

Peptaibol Analogs Show Potent Antibacterial Activity against Multidrug Resistant Opportunistic Pathogens.

New classes of antibacterial drugs are urgently needed to address the global issue of antibiotic resistance. In this context, peptaibols are promising membrane-active peptides since they are not involved in innate immunity and their antimicrobial activity does not involve specific cellular targets, therefore reducing the chance of bacterial resistance development. Trichogin GA IV is a nonhemolytic, natural, short-length peptaibol active against Gram-positive bacteria and resistant to proteolysis.

Discovery and Optimization of a Novel Macrocyclic Amidinourea Series Active as Acidic Mammalian Chitinase Inhibitors.

Our research group has been involved for a long time in the development of macrocyclic amidinoureas (MCAs) as antifungal agents. The mechanistic investigation drove us to perform an target fishing study, which allowed the identification of chitinases as one of their putative targets, with showing a submicromolar inhibition of chitinase. In this work, we investigated the possibility to further inhibit the corresponding human enzymes, acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1), involved in several chronic inflammatory lung diseases.

Benzenesulfonamide derivatives as carbonic anhydrases inhibitors: a computational-aided insight in the structural rigidity-activity relationships.

causes life-threatening infections in low-income countries due to the rise of antibacterial resistance. Innovative pharmacological targets have been investigated and carbonic anhydrases (CAs, EC: 4.2.

Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller MM109.

strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of .

Chemical Optimization of Selective LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models.

LasB elastase is a broad-spectrum exoprotease and a key virulence factor of , a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies.

Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant .

The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant as a "critical priority" for the discovery and development of new antibacterial agents.

Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.

Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition ( = 10-30 nM).

A Clinical Study Provides the First Direct Evidence That Interindividual Variations in Fecal β-Lactamase Activity Affect the Gut Mycobiota Dynamics in Response to β-Lactam Antibiotics.

Antibiotics disturb the intestinal bacterial microbiota, leading to gut dysbiosis and an increased risk for the overgrowth of opportunistic pathogens. It is not fully understood to what extent antibiotics affect the fungal fraction of the intestinal microbiota, the mycobiota. There is no report of the direct role of antibiotics in the overgrowth in healthy humans of the opportunistic pathogenic yeast Candida albicans.

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas.

Trifluoroacetic acid (TFA), due to its strong acidity and low boiling point, is extensively used in protecting groups-based synthetic strategies. Indeed, synthetic compounds bearing basic functions, such as amines or guanidines (commonly found in peptido or peptidomimetic derivatives), developed in the frame of drug discovery programmes, are often isolated as trifluoroacetate (TF-Acetate) salts and their biological activity is assessed as such in in vitro, ex vivo, or in vivo experiments. However, the presence of residual amounts of TFA was reported to potentially affect the accuracy and reproducibility of a broad range of cellular assays (e.

1,2,4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors.

Metallo-β-lactamases (MBLs) represent an increasingly serious threat to public health because of their increased prevalence worldwide in relevant opportunistic Gram-negative pathogens. MBLs efficiently inactivate widely used and most valuable β-lactam antibiotics, such as oxyiminocephalosporins (ceftriaxone, ceftazidime) and the last-resort carbapenems. To date, no MBL inhibitor has been approved for therapeutic applications.

A fragment-based drug discovery strategy applied to the identification of NDM-1 β-lactamase inhibitors.

Hydrolysis of β-lactam drugs, a major class of antibiotics, by serine or metallo-β-lactamases (SBL or MBL) is one of the main mechanisms for antibiotic resistance. New Delhi Metallo-β-lactamase-1 (NDM-1), an acquired metallo-carbapenemase first reported in 2009, is currently considered one of the most clinically relevant targets for the development of β-lactam-β-lactamase inhibitor combinations active on NDM-producing clinical isolates. Identification of scaffolds that could be further rationally pharmacomodulated to design new and efficient NDM-1 inhibitors is thus urgently needed.