Chemical Optimization of Selective Pseudomonas aeruginosa 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 Pseudomonas aeruginosa, 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 P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1 beta. Furthermore, inhibition of LasBmediated IL-1 beta activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen

SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem

Etude de la régulation des fonctions bactéricides des macrophages par les mycobactéries

Les mycobactéries pathogènes sont capables de survivre et de se multiplier à l'intérieur des macrophages en régulant leurs réponses bactéricides. Ceci implique que les mycobactéries aient développé des mécanismes de résistance. Dans les macrophages " au repos ", les mycobactéries survivent à des temps précoces d'infection et ceci est régulé par un événement récepteur-dépendant. Les mycobactéries empruntent des récepteurs de phagocytose non opsoniques qui ne déclenchent pas des réponses bactéricides. Le CR3 est une nouvelle voie d'entrée non opsonique des mycobactéries sous réserve de son activation. C'est une voie d'entrée silencieuse. A des étapes tardives d'infection, seules les mycobactéries pathogènes comme M. tuberculosis sont capables de survivre. Cela nécessite la mise en place de facteurs de virulence. La protéine tyrosine phosphatase MptpA de M. tuberculosis est capable d'inhiber la phagocytose de mycobactéries pathogènes et non pathogènes.Pathogenic mycobacteria can survive and multiply into macrophages by regulating bactericidal responses. It implies that mycobacteria developped resistance mecanisms. In resting macrophages, mycobacteria survive at early time of infection and that is regulated by receptor-dependent event. Mycobacteria use non-opsonic phagocytosis receptors that are uncoupled from bactericidal responses. CR3 participates in the non-opsonic uptake of mycobacteria and depend on the state of receptor activation. CR3 is a new safe portal of entry. At late time of infection, pathogenic mycobacteria like M. tuberculosis survive in macrophages. This implies synthesis of virulence factors. The tyrosine phosphatase MptpA of M. tuberculosis inhibits phagocytosis of pathogenic and non pathogenic mycobacteria.TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Discovery of a Novel Metallo-β-Lactamase Inhibitor that Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacteriaceae

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1. MBL-producing strains are endemic within the community in many Asian countries, have successfully spread worldwide, and account for many significant CRE outbreaks. Recently approved combinations of β-lactam antibiotics with β-lactamase inhibitors are only active against SBL-producing pathogens. Therefore, new drugs that specifically target MBLs and which restore carbapenem efficacy against MBL-producing CRE pathogens are urgently needed. Here, we report the discovery of a novel MBL inhibitor, ANT431, that can potentiate the activity of MEM against a broad range of MBL-producing CRE, and restore its efficacy against anEscherichia coliNDM-1 strain in a murine thigh infection model. This is a strong starting point for a chemistry lead optimization program that could deliver a first-in-class MBL inhibitor/carbapenem combination. This would complement the existing weaponry against CREs and address an important and growing unmet medical need

Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO “critical priority pathogen” producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure–activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.Peer reviewe